Evaluation of Iron Status in Patients of Solid Organ Malignancies: Study from a Cancer Research Centre

Abstract

Anemia associated with cancer is a major public health issue. The gravity of this problem is likely to be higher in India due to already existing malnutrition in the general population. Iron deficiency anemia (IDA) as a subset has not been evaluated in Indian population of cancer patients. This study was undertaken to evaluate iron status among newly diagnosed advanced-stage cancer patients with anemia at a cancer research institute in India. Sixty-four patients of anemia were identified who fulfilled the inclusion criteria. Iron status was noted. Absolute iron deficiency (AID) was identified in 8 (12.5%) patients. Functional iron deficiency (FID) was seen in 48 (75%) patients. Probable functional iron deficiency (PFID) was seen in 2 (3.1%) patients while no iron deficiency (NID) was seen in 6 (9.3%) patients. FID is seen in majority of advanced-stage solid organ cancer patients in India. Large sample studies are required to better define the exact prevalence of iron deficiency, chemotherapy-induced anemia, and anemia in cancer subtypes.

Introduction

Anemia is a frequent co-morbidity in patients suffering from cancer. It is usually associated with impaired physical activities, generalized weakness, lethargy, and fatigue. Anemia remains under-recognized and poorly managed in cancer patients. It not only affects the health-related quality of life (QOL) but also hampers the optimum delivery of chemotherapy. It is, therefore, important to recognize the cause of anemia in cancer patients in order to provide the appropriate treatment. Moreover, anemia has been considered as an adverse prognostic factor as it is associated with shorter survival [1].

The prevalence of anemia in cancer patients has been variably reported from 40% in early disease to 80% in advanced disease [2]. The European Cancer Anemia Survey (ECAS) reported the prevalence of anemia in cancer patients at enrolment as 39.3% [3]. Anemia also develops as a result of chemotherapy. In chemotherapy-treated patients, the incidence has been shown as high as 91.5% [4].

Anemia in cancer patients may occur as a direct effect of cancer due to suppression of hematopoiesis through bone marrow infiltration, by the production of cytokines that lead to iron sequestration, by reduced red blood cell production, or by induced by chemotherapy [5]. However, anemia in a treatment-naive cancer patient can be multifactorial such as blood loss, hemolysis, hypersplenism, nutrient deficiencies, and chronic kidney disease (CKD) and not always anemia of chronic disease (ACD). Various other factors like type and stage of the cancer, duration of the illness, and concomitant infectious conditions may also contribute to anemia. Chemotherapy and/or radiotherapy further aggravate the anemia. Early identification and treatment of anemia prior to the start of chemotherapy and/or radiotherapy, therefore, is necessary. Anemia associated with cancer can be due to iron deficiency. In a developing country like India, nutritional deficiency anemia is also widely prevalent. Iron supplementation in such cases can increase hemoglobin level substantially thus obviating the need for blood transfusion; however, prior evaluation of AID and FID is necessary as therapeutic modalities for these conditions may differ. Our knowledge regarding the prevalence of anemia, AID, and FID in cancer patients is scarce, and only a few studies are available [6, 7]. Moreover, there is scarcity of data regarding evaluation of anemia associated with malignancy as far as Indian population is concerned.

The incidence of anemia increases with the stage of the disease [8]. Higher tumor burden corresponds to an increased inflammatory state which leads to the development of anemia and FID. A large number of patients of advanced-stage cancer who are treatment naïve present to us. As a routine, all patients undergo a comprehensive evaluation for anemia at our institute prior to commencing anti-definite anti-cancer therapy. This led us to pursue the evaluation of iron status in solid organ cancer patients of advanced stage.

Patients and Methods

It was a retrospective study. A total of 64 patients diagnosed with advanced-stage solid organ malignancies of age 18 years and above, having hemoglobin (Hb) level of ≤ 11 g/dL in both males as well as females [9], and who were chemotherapy as well as radiotherapy naive were included during the study period (February 2018–January 2019). The exclusion criteria included (1) patients receiving hematinic and/or nutritional supplements, (2) patients who had received blood transfusion or some form of erythropoiesis-stimulating agents (ESAs) after the symptoms onset, (3) patients with concomitant chronic illness like end-stage renal disease, chronic liver disease, chronic rheumatological disorder, chronic heart disease, or hemoglobinopathies, (4) patients with hematological malignancies, (5) patients with a diagnosis of hemolytic anemia, and (6) patients with a diagnosis of megaloblastic anemia. Age, sex, performance status (PS), type of cancer, and stage of cancer were assessed for each patient. Complete blood counts, peripheral blood smear morphology, serum iron, serum ferritin, total iron-binding capacity (TIBC), and transferrin saturation (TS) estimation were noted. Recognized definitions for anemia, AID, FID, PFID, and NID were used [9, 10]. AID was defined as TS < 20% and serum ferritin < 30 ng/mL. FID was defined as TS < 50% and serum ferritin 30–500 ng/mL. PFID was defined as TS < 50% and serum ferritin > 500–800 ng/mL while NID was defined as TS ≥50% or serum ferritin > 800 ng/mL. PS was defined as per the Eastern Cooperative Oncology Group (ECOG) criteria [11]. Mild, moderate, and severe anemia was defined as per the National Cancer Institute Anemia Scale [12]. Descriptive statistics was used to analyze the data.

Results

A total of 64 patients were found to be eligible during the study period. These included 37 male and 27 female patients. The mean age of the study group was 63.33 years (25–85 years). The Hb level ranged from 6.7 to 11 g/dL. Mild, moderate, and severe anemia was seen in 35 (54.7%), 24 (37.5%), and 5 (7.8%) patients, respectively. Poor PS (ECOG 2–4) was seen in 51 (79.67%) patients. AID was identified in 8 (12.5%) patients. FID was seen in 48 (75%) patients. PFID was seen in 2 (3.1%) patients while NID was seen in 6 (9.3%) patients (Table 1).

Table 1.

Results of the study

Characteristics (n = 64)	Number (range)
Mean age (years)	63.33 (25–85)
Males	37
Females	27
Site of primary
Lung	23
Hepato-pancreatico-biliary	13
Gastro-intestinal	7
Female genito-urinary	5
Male genito-urinary	5
CUP	3
Head and neck	2
Breast	2
Sarcoma	2
Mesothelioma	2
ECOG (PS)
1	12
2	25
3	19
4	7
Anemia grade
1 (mild)	35
2 (moderate)	24
3 (severe)	5
Iron status
AID	8
FID	48
PFID	2
NID	6

Abbreviations: CUP cancer of unknown primary, ECOG Eastern Cooperative Oncology Group, PS performance status, AID absolute iron deficiency, FID functional iron deficiency, PFID probable functional iron deficiency, NID no iron deficiency

Discussion

Anemia is frequently encountered in patients with solid organ malignancies of advanced stage, and a diligent evaluation is necessary prior to initiating any definite therapy as it can have therapeutic implications. Iron deficiency in anemia can be classified as absolute, when iron reserves are exhausted, or functional, when the reserves are optimum or increased. Under these circumstances, iron is not available for erythropoiesis which leads to anemia. FID is the predominant physiological state in cancer patients as iron is trapped inside macrophages and is not available for erythropoiesis [13]. Hashemi et al. in their study demonstrated AID in 12.5%, FID in 53.2%, and NID in 34.4% of patients. No significant differences were observed among the various stages of cancers in terms of degrees of iron deficiency [14]. Neoh et al. estimated the prevalence of FID anemia in advanced cancer. They found that anemia was common in advanced-stage disease patients and the prevalence of FID was 39–43%. Prevalence of FID anemia varied significantly by tumor site and was highest in patients with genitourinary, colorectal, melanoma, and head and neck cancers [15]. There is a common notion among clinicians that cancer patients usually have anemia of chronic disease which is not true. Kanuri et al. reported 60% incidence of IDA in their study and concluded that IDA coexists with cancer-related anemia and adversely affects quality of life [16]. We found AID in 12.5% of the patients and these are the candidates for intravenous (IV) or oral iron supplementation. Seventy-five percent patients were having FID in which IV iron supplementation is necessary followed by ESAs if required. NID was diagnosed in 9.3% patients, and these are candidates for transfusion support primarily. Appropriate diagnosis of AID, FID, PFID, and NID is important as these different identities have different management. Moreover, intravenous iron therapy alone can resolve anemia in patients with FID and lymphoid malignancies undergoing chemotherapy [17]. IV iron therapy and treatment with ESAs have been associated with improved PS and QOL [18]. Current guidelines for cancer-associated anemia recommend judicious use of blood transfusion support and restricted use of erythropoietic therapy to those patients in which the intent of treatment is only palliative, based upon the safety concerns associated with both treatments. It is, therefore, necessary to assess iron status in cancer patients as a routine [10].

Limitations of the Study

It was a retrospective study. Due to the smaller sample size, stratification of iron status as per different types of cancers and further evaluation was not done.

Conclusion

There is a wide spectrum of patients suffering from AID, FID, and NID which affects their QOL and have impact on timely delivery of chemotherapy and thus poorer outcomes. It is important to distinguish between these conditions as the management is not same for all and depends upon the iron status. Assessment of the iron status of cancer patients is thus necessary. Further large sample studies are warranted to define the exact prevalence of AID, FID, chemotherapy-induced anemia, and anemia in different types of cancer.

Author Contributions

DS, LA, and RS were involved in the data collection. PPN, MW, and DS wrote the manuscript. DS and LA reviewed the final manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.