Anemia in malignant neoplasms: clinical guidelines

List of Abbreviations

CRA – anemia in malignant neoplasms

ID – iron deficiency

GI – gastrointestinal tract

ESA – erythropoiesis-stimulating agents (B03XA: Other antianemic preparations)

LCS – lower gastrointestinal series / fibrocolonoscopy

EGD – esophagogastroduodenoscopy

ECOG – Eastern Cooperative Oncology Group Scale of Performance Status, a scale used to assess a patient's overall functioning developed by the Eastern Cooperative Oncology Group

Hb – hemoglobin

Hct – hematocrit

MCV – mean corpuscular volume

MCH – mean corpuscular hemoglobin

MCHC – mean corpuscular hemoglobin concentration

CTCAE – Common Terminology Criteria for Adverse Events

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

Anemia of cancer (AC) is a decrease in hemoglobin (Hb) concentration and/or red blood cell count below normal values, including that caused by the tumor process and/or its treatment.

Erythropoiesis-stimulating agents (ESAs, B03XA: Other antianemic preparations) are a group of medicinal products that stimulate the formation of red blood cells in the bone marrow, used for the treatment of anemias.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Anemia of cancer (AC) is defined as a decrease in Hb concentration and/or red blood cell count below normal values, including that caused by the tumor process and/or its treatment.

The consequences of anemia may include a compromised response to cancer therapy and decreased overall survival (OS), even if a direct causal relationship is not established [1,2], as well as a reduced quality of life in patients due to varying degrees of impaired exercise tolerance and anemia-related symptoms.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Causes of cancer-related anemia include [3–5]:

1. Chronic inflammation due to the effect of pro-inflammatory tumor cytokines on hematopoiesis and iron metabolism

2. Myelosuppression and red blood cell destruction resulting from the cytotoxic effect of antitumor therapy (drug therapy, radiation therapy)

3. Suppression of hematopoiesis and erythroid progenitor cell differentiation in the bone marrow by the tumor process or antitumor treatment

4. Impaired erythropoietin synthesis, as well as decreased sensitivity of erythroid progenitor cells to erythropoietin

5. Bone marrow infiltration by tumor cells resulting in hematopoietic space reduction

Additional factors contributing to the development or worsening of anemia in cancer patients may include:

1. Acute and chronic bleeding

2. Iron deficiency states

3. Vitamin B12 deficiency (including those caused by antibodies to intrinsic factor of Castle) and folate deficiency states

4. Renal impairment with decreased erythropoietin production

5. Hemolysis (increased destruction of erythroid cells) due to autoimmune reactions, microangiopathy, and other causes

Thus, the pathogenesis of anemia in cancer patients is rather complex and is associated with both direct and indirect effects of the tumor process on the body, as well as the potential suppressive effect of antitumor treatment on the erythroid hematopoietic lineage in some cases [4].

1.3 Epidemiology of the Disease or Condition

Anemia and iron deficiency (ID) are frequent complications in patients with malignant neoplasms, especially those receiving antineoplastic agents [6]. According to the European Cancer Anemia Survey (ECAS), among 15,000 analyzed cancer patients at the time of diagnosis, the incidence of anemia was 39.3%, and the administration of specialized therapy increased the incidence of anemia in these patients to 67.0% [7,8].

1.4 Features of Coding the Disease or Condition

D63.0 – Anemia in neoplastic disease

1.5 Classification of the disease or condition

For the differential diagnosis of anemias, a number of classifications based on various criteria are used, including: morphological characteristics of red erythrocytes (specifically MCV, MCH, and MCHC values); the capacity of the bone marrow to produce red blood cells (determined based on relative and absolute reticulocyte counts), the degree of hemoglobin concentration reduction, and others [9]

Based on mean corpuscular volume (MCV) and mean corpuscular hemoglobin / concentration (MCH, MCHC), anemias are classified into:

1. Microcytic and hypochromic anemias (MCV <80 fl, MCH <27 pg, MCHC <300 g/L);

2. Normocytic and normochromic anemias (MCV 80-100 fl, MCH 27 – 34 pg, MCHC 300 -380 g/L);

3. Macrocytic and hyperchromic anemias (MCV >100 fl, MCH >34 pg, MCHC >380 g/L).

According to the bone marrow regenerative capacity, the following are distinguished:

1. Hyporegenerative anemias (rel. Ret <0.5%, abs. Ret <20 × 10⁹/L);

2. Normoregenerative anemias (rel. Ret 0.5–2.0%, abs. Ret 20 - 100 × 10⁹/L);

3. Hyperregenerative anemias (rel. Ret >2%, abs. Ret > 100 × 10⁹/L).

Typical morphological features and regeneration characteristics of the most common anemia variants are presented in Tables 1 and 2.

Table 1. Morphological classification of anemias (based on MCV and MCH/MCHC values)

Table 2. Classification of anemias based on regenerative capacity

According to WHO criteria, anemia severity is classified as follows [10]:

1. Mild anemia: hemoglobin concentration 100–119 g/L in women and 100–129 g/L in men;

2. Moderate anemia: hemoglobin concentration 80–99 g/L in both sexes;

3. Severe anemia: hemoglobin concentration <80 g/L in both sexes.

To assess the toxicity grade of medicinal products (including cytostatic effects), the CTCAE scale presented in Appendix G2 is used.

1.6 Clinical presentation of the disease or condition

The main clinical symptoms of anemia may include pallor of the skin and mucous membranes, palpitations (tachycardia), shortness of breath (tachypnea), asthenia, tinnitus, and headache.

Anemia is often associated with fatigue, impaired physical function, and reduced quality of life [11–13].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended methods for diagnosing the disease and related conditions have a limited evidence base (according to the criteria of the scales for assessing the level of reliability of evidence and the level of clinical recommendation validity) due to the lack of clinical studies dedicated to them. Despite this, they are necessary elements of patient examination to establish a diagnosis and choose treatment tactics, as more effective and proven methods have not yet been developed.

Anemia in malignancies may be suspected based on anamnesis data and physical examination results; it is established based on the results of laboratory tests.

The main diagnostic criterion for anemia is a persistent decrease in hemoglobin concentration below 120 g/L in women and below 130 g/L in men [10].

2.1 Complaints and Anamnesis

• All patients with suspected cancer-related anemia and all patients with a confirmed diagnosis of cancer-related anemia are recommended to undergo history taking and symptom assessment at each medical appointment to evaluate the patient's condition and identify potential alternative causes of anemia [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: when collecting complaints and anamnesis in patients with anemia, it is necessary to assess the possibility of other causes of anemia, in particular:

• acute or chronic bleeding;

• hemolysis (autoimmune, microangiopathic);

• intercurrent diseases (e.g., infectious and inflammatory diseases, kidney diseases, etc.);

• iron, folic acid, vitamin B12 deficiency;

• hereditary anemia (including hemoglobinopathies).

2.2 Physical Examination

• All patients with suspected cancer-related anemia and all patients with a confirmed diagnosis of cancer-related anemia are recommended to undergo visual examination, palpation, and percussion for hematopoietic and blood diseases [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: General physical examination implies assessing the patient's general condition using the Eastern Cooperative Oncology Group – ECOG performance status scale (Appendix G1), the presence of hypoxia symptoms, and the degree of compensation of theemic syndrome.

The physical examination evaluates:

• color of the skin and visible mucous membranes (pallor, jaundice);

• changes in the cardiovascular system (tachycardia, muffled heart sounds, heart murmurs);

• changes in the respiratory system (tachypnea);

• severity of asthenia, exercise tolerance.

In patients with cancer-related anemia, most complaints and clinical symptoms are nonspecific and, as a rule, are combined with complaints and clinical manifestations of the underlying disease (tumorous process), as well as adverse events of ongoing specialized therapy (drug therapy, radiation therapy).

It should be noted that the onset of infection, hyperthermia, or pain can lead to decompensation of theemic syndrome. Signs of decompensation may include labored, rapid breathing with intercostal, subcostal, and suprasternal retractions (respiratory distress); increased use of abdominal muscles for breathing; nasal flaring; forced ("groaning") exhalation (respiratory distress); altered mental status; weakened peripheral pulse; congestive heart failure (hepatomegaly, edema).

2.3 Laboratory Diagnostics

• All patients with suspected cancer-related anemia and all patients with a confirmed diagnosis of cancer-related anemia are recommended to undergo laboratory and instrumental examinations to detect anemia, determine its type, clarify the severity of anemia, and identify the leading etiological factors [4]. Diagnosis of anemia and identification of its causes must be carried out prior to blood transfusion (unless there are emergency indications) or the administration of erythropoiesis-stimulating agents (ESAs; B03XA: Other antianemic preparations) and iron preparations [4,14].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with clinical symptoms of cancer-related anemia are recommended to undergo a complete blood count (CBC) with differential, determining total blood hemoglobin, red blood cell and reticulocyte counts, hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) [15].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: considering that most symptoms of anemia are nonspecific, the most accessible, objective, and fundamental method for diagnosing anemia is the laboratory determination of blood hemoglobin concentration. Cancer-related anemia is typically hyporegenerative, normocytic, and normochromic in nature.

• Patients with clinical and laboratory manifestations of cancer-related anemia are recommended to undergo iron metabolism studies, including serum iron, serum ferritin, serum transferrin, total iron-binding capacity (TIBC), transferrin saturation (TSAT), and serum C-reactive protein (CRP), to determine the type of anemia and perform differential diagnosis with iron deficiency anemia [15–17].

Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)

Comments: iron deficiency anemia typically presents as a normoregenerative (or hyperregenerative in ongoing blood loss) microcytic, hypochromic anemia, whose characteristic laboratory feature is a serum ferritin concentration <30 ng/mL [17,18]In the case of a concomitant inflammatory process (tumor-induced or of other origin) and an elevated CRP concentration >5 mg/L, the criteria for absolute iron deficiency are a serum ferritin concentration <100 ng/mL combined with a decreased TSAT <20 % [19]. A serum ferritin value >100 ng/mL combined with a TSAT <20 % is regarded as functional (reticuloendothelial) iron deficiency – a condition characterized by iron sequestration in export cells (enterocytes, hepatocytes, macrophages) and reduced iron transport to consumer cells, leading to iron-deficient erythropoiesis despite adequate tissue iron stores [19]. In complex clinical situations, in addition to determining ferritin concentration and calculating TSAT, it is necessary to assess transferrin concentration and total iron-binding capacity (TIBC). Absolute iron deficiency is characterized by increased serum transferrin concentration and TIBC, whereas inflammatory changes are characterized by normal or decreased transferrin concentration and normal TIBC [20]

• Patients in whom clinical and laboratory manifestations suggest vitamin B12 deficiency or folate deficiency anemia are recommended to have blood vitamin B12 (cyanocobalamin) and serum folic acid levels determined [4,21,22].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: vitamin B12 and folate deficiency anemias are characterized by macrocytosis and hyperchromia of red blood cells, a normal or reduced reticulocyte count, a picture of megaloblastic erythropoiesis in the bone marrow, decreased platelet and leukocyte counts (up to profound pancytopenia), hypersegmentation of neutrophil nuclei, as well as laboratory signs of hemolysis. Vitamin B12 deficiency anemia is typically characterized by nervous system involvement [23,24]

• Patients in whom clinical and laboratory manifestations suggest hemolytic anemia are recommended to undergo hemolysis tests (total blood bilirubin, free (unconjugated) and conjugated blood bilirubin, blood lactate dehydrogenase (LDH) activity, blood haptoglobin, and direct antiglobulin test (direct Coombs test)) [25].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: General laboratory characteristics of hemolytic anemias include reticulocytosis (relative and absolute), elevated bilirubin due to the indirect fraction, elevated LDH, and decreased serum haptoglobin. In autoimmune hemolysis, a positive direct Coombs test is registered. Bone marrow examination in hemolytic anemias reveals erythroid hyperplasia of hematopoiesis [26]

• For patients in whom clinical and laboratory manifestations suggest occult gastrointestinal bleeding, a fecal occult blood test is recommended [15].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• For patients in whom clinical and laboratory manifestations suggest renal impairment, measurement of blood creatinine and/or nephron function via creatinine clearance (Rehberg's test) is recommended [27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• For patients in whom clinical and laboratory manifestations suggest myelodysplastic syndrome or impaired renal erythropoietin production, measurement of blood erythropoietin levels is recommended [27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Myelodysplastic syndrome is a group of clonal hematopoietic stem cell disorders characterized by cytopenia, bone marrow dysplasia, and a high risk of transformation into acute leukemia. The presence of refractory anemia (after ruling out anemias of other etiologies) combined with thrombocytopenia and/or leukopenia allows for suspected myelodysplastic syndrome. Anemia in myelodysplastic syndrome is characterized by normocytic (or macrocytic in certain forms) erythrocytes and a normal or decreased reticulocyte count. Iron metabolism parameters show tissue iron overload: serum ferritin >300 ng/mL, transferrin saturation >45%, decreased serum transferrin, and reduced total iron-binding capacity (TIBC) [28].

2.4 Instrumental Diagnostics

• For patients with a confirmed diagnosis of iron deficiency anemia occurring against the background of a malignant neoplasm, endoscopic examinations of the upper and lower gastrointestinal tract (esophagogastroduodenoscopy, colonoscopy) are recommended to rule out bleeding and take measures to stop it [4,15].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• For patients with a confirmed diagnosis of iron deficiency anemia occurring against the background of a malignant neoplasm, instrumental examinations are recommended to locate the source of blood loss. Depending on the volume and localization of the tumor lesion, the following are performed [4,15]:

• chest X-ray and targeted chest X-ray;

• abdominal plain radiography;

• computed tomography of the chest;

• computed tomography of the abdomen;

• computed tomography of the pelvis;

• ultrasound of the chest;

• complex ultrasound of the abdomen, complex ultrasound of the pelvis, ultrasound of soft tissues (one anatomical zone), ultrasound of the kidneys, and other areas (as indicated);

• esophagogastroduodenoscopy;

• colonoscopy;

• bronchoscopy;

• laryngoscopy;

• pharyngoscopy.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Diagnosis of anemia and identification of its causes must be performed prior to blood transfusion (unless there are emergency indications for transfusion) or the administration of erythropoiesis-stimulating agents (ESAs; B03XA: Other antianemic preparations) and iron supplements.

2.5 Other Procedures

• For patients with suspected anemia caused by impaired bone marrow hematopoiesis, bone marrow metastases, or other causes unrelated to the primary malignant disease, bone marrow examination is recommended [29].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: Bone marrow aspiration (obtaining a bone marrow cytologic specimen via puncture) for cytologic examination of a bone marrow smear (myelogram) and/or trephine biopsy (obtaining a bone marrow histologic specimen) for pathomorphological examination of biopsy (surgical bone marrow) material can be performed as indicated.

• For all patients with anemia of chronic disease (ACD), blood group and Rh factor testing is recommended [30].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: determination of the main blood groups using the AB0 system, determination of the D antigen of the Rhesus system (rhesus factor), determination of the phenotype by C, c, E, e, C^w, K, k antigens and determination of anti-erythrocyte antibodies, and other tests according to indications.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.1.1 Red blood cell mass transfusion

• For patients with a hemoglobin concentration below 70 g/L and/or clinical manifestations ofemic hypoxia (including at higher hemoglobin levels), transfusion of red blood cell components of donor blood (packed red blood cells, leukoreduced red blood cells, apheresis red blood cells, etc.) is recommended [14,31].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: Blood transfusions are prescribed based on clinical indications, with hemoglobin concentration serving as one of the reference points. Thus, transfusions of red blood cell components may be indicated in milder anemia with a hemoglobin level of 100–80 g/L if extensive surgery is planned, if anemia leads to hypoxic symptoms, etc.

Red blood cell components of donor blood are donor blood components obtained after centrifugation of whole donor blood by removing the maximum amount of plasma and, in some cases, the buffy coat, thereby containing predominantly erythrocytes (packed red cells, red blood cell suspension, etc.).

Replacement transfusions of red blood cell components are a traditional method for correcting reduced Hb and life-threatening situations associated with acute blood loss (major surgeries). However, for the treatment of anemia associated with a tumor process (tumor breakdown, intoxication) and antitumor treatment, transfusions are not an unambiguously safe and effective method. Transfusions may be accompanied by hemolytic reactions, including fatal ones (frequency 1:1,000), transfusion-related acute lung injury (TRALI) (frequency 1:5,000), bacterial contamination, including fatal sepsis (frequency 1:10,000), transmission of hepatitis B virus (frequency 1:30,000), hepatitis C virus, and human immunodeficiency virus (frequency 1:1,000,000) [33, 34]. Furthermore, many potentially dangerous viral infections are currently not screened for in donors. Along with the above, transfusion-induced immunosuppression leads to an increased risk of thrombosis, infectious complications, and reduced relapse-free and overall survival in a number of malignancies (colorectal cancer, bladder cancer) [32,33]The increase in Hb concentration following transfusions is short-lived, and they must be repeated to maintain normal values. Therefore, the WHO recommends strictly regulating replacement transfusions in cancer patients and utilizing alternative methods for Hb correction.

In accordance with Order No. 348n of the Ministry of Health of the Russian Federation dated June 3, 2013, transfusions for Hb <70–80 g/L are indicated only in cases of acute posthemorrhagic anemia with a simultaneous drop in hematocrit to ≤25%. In chronic anemias, the primary objective is to eliminate the underlying cause, and transfusions are prescribed solely to correct clinically significant symptoms caused by hypoxia due to reduced Hb that are refractory to pathogenetic therapy. Thus, Hb concentration in isolation cannot serve as an absolute criterion for the necessity of blood transfusions; therefore, the decision must always be the result of the attending physician's clinical judgment, based primarily on objective signs of hypoxia, taking into account concomitant risk factors (bleeding, intercurrent infections, upcoming chemo/radiotherapy, etc.). For patients requiring frequent transfusions, irradiated, leukocyte-depleted red blood cells are preferred. Leukoreduction has been shown to significantly reduce the risk of febrile non-hemolytic transfusion reactions and the transmission of infectious agents [34,35]. Irradiation of red blood cells prevents the development of transfusion-associated graft-versus-host disease in immunocompromised patients [34,36].

3.1.2 Pharmacotherapy to correct CRA

• For patients with symptomatic anemia or a hemoglobin level below 100 g/L, pharmacotherapy with erythropoiesis-stimulating agents (ESAs, B03XA: Other antianemic preparations) as monotherapy or in combination with iron supplements is recommended [13,15,29,37,38]

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: the use of ESAs (B03XA: Other antianemic preparations) may be indicated for symptomatic anemia, Hb <100 g/L, and in all patients with severe anemia. If there is no response (an increase in Hb of less than 10 g/L with a baseline Hb <100 g/L), treatment with ESAs (B03XA: Other antianemic preparations) should be discontinued after 8 weeks. The use of ESAs (B03XA: Other antianemic preparations) increases bone marrow erythropoiesis and raises Hb levels without the need for donor erythrocyte transfusions. Controlled trials have shown that using ESAs (B03XA: Other antianemic preparations) in cancer-related anemia and chemotherapy-induced anemia increases Hb concentration in 60–70% of cases and is accompanied by a significant reduction in the need for red blood cell transfusions (relative risk 0.64; 95% CI 0.6–0.68). In patients with solid tumors and those receiving platinum-based chemotherapy, the use of ESAs (B03XA: Other antianemic preparations) is more effective than in other tumor types and chemotherapy regimens. Several studies have demonstrated an improvement in quality of life with ESA therapy (B03XA: Other antianemic preparations). However, other studies found differences in quality of life scores to be insignificant.

The use of ESAs (B03XA: Other antianemic preparations) increases the probability of venous thromboembolic events (VTEs), raising the relative risk by 67% compared to placebo (RR 1.67; 95% CI: 1.35–2.06) [39]. However, the administration of erythropoietins does not require additional VTE prophylaxis. The impact of ESAs (B03XA: Other antianemic preparations) on the survival of cancer patients is being studied, but study results are ambiguous. Data from three meta-analyses showed a negative impact of ESAs (B03XA: Other antianemic preparations) on overall survival, whereas the results of two other meta-analyses showed no such effect. However, none of the meta-analyses revealed a significant negative impact of ESAs (B03XA: Other antianemic preparations) in patients receiving chemotherapy. Therefore, most experts consider the use of ESAs (B03XA: Other antianemic preparations) inappropriate in patients not receiving chemotherapy or chemoradiotherapy.

Contraindications to the use of ESAs (B03XA: Other antianemic preparations):

• known hypersensitivity to ESAs (B03XA: Other antianemic preparations) or their components;

• uncontrolled arterial hypertension;

• high risk of thromboembolic events (history of thrombosis, major surgery, prolonged immobilization or restricted activity, treatment with lenalidomide** in combination with doxorubicin** and glucocorticoids; data on the role of prophylactic anticoagulation are lacking).

Recommended doses of ESAs (B03XA: Other antianemic preparations) and correction principles in adult cancer patients receiving chemotherapy are presented in Table 1 (see Appendix A3).

• Patients with proven absolute iron deficiency are recommended to receive iron preparations in accordance with iron deficiency anemia treatment protocols [13,19,40].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: in some patients, intensified erythropoiesis resulting from ESA therapy (B03XA: Other antianemic preparations) leads to absolute iron deficiency, necessitating baseline and dynamic monitoring of iron metabolism parameters in patients with cancer-related anemia.

The choice of the preferred dosage form (oral or parenteral) and the dose of iron preparation depend on several factors: the severity of anemia, the presence of concomitant inflammation (particularly associated with the tumor process), ongoing blood loss, and individual tolerance to various iron formulations.

In mild to moderate anemia without ongoing blood loss and with normal CRP levels, it is advisable to correct iron deficiency using oral iron preparations at a dose of 60–120 mg of elemental iron daily or on an alternate-day schedule. The duration of therapy is determined by the severity of the initial iron deficiency and can range from 1 to 3 months (or longer in some cases) until the laboratory presentation of iron deficiency anemia resolves (ferritin 40–60 ng/mL with CRP <5 ng/mL).

In severe anemia, ongoing blood loss (which cannot be stopped by surgical and/or conservative methods), and elevated CRP >5 ng/mL (associated with the tumor process), treatment with parenteral trivalent iron preparations is indicated.

In the presence of infectious complications, the use of both oral and intravenous iron preparations is postponed until the infection is resolved.

Due to potential interactions between iron and certain antineoplastic agents (anthracyclines and related compounds, platinum agents), iron administration should be avoided on the days of chemotherapy administration. Recommended doses and regimens for parenteral iron administration are presented in Table 2 (see Appendix A3).

• Patients who develop autoimmune hemolytic anemia secondary to malignant neoplasms are recommended to undergo therapy in accordance with autoimmune hemolytic anemia treatment protocols [41,42].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: in some cases, the development of autoimmune hemolysis, such as in lymphoproliferative disorders, is an indication for specific chemotherapy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

No specific rehabilitation or spa-treatment methods have been developed for patients with cancer-related anemia. Rehabilitation for these patients should be comprehensive, encompassing social, neuropsychological, and clinical-psychological adaptation. The scope of medical rehabilitation is developed individually for each patient by a rehabilitation physician and medical psychologist, with the participation of an oncologist and hematologist. Additionally, the rehabilitation program must account for the patient's social and psychological challenges and involve social workers and psychologists (as indicated). Rehabilitation for complications arising during the disease and its treatment is carried out within the framework of the respective nosologies.

5. Prevention and Dispensary Observation

No specific methods of prevention and follow-up (dispensary observation) have been developed for patients with cancer-related anemia. Timely detection of cancer-related anemia requires regular complete blood count monitoring during therapy and follow-up regarding the primary disease (malignant neoplasm).

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation," is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized Federal Executive Authority;

2) in accordance with the procedure for the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;

3) in accordance with the procedure for providing care in the specialty of "hematology", mandatory for implementation throughout the Russian Federation by all medical organizations for ICD-10 codes: C81–C96, D45–D47, D50–D76, E75.2, E80.0, E80.2, E83.0, E83.1, E85.8, M31.1;

4) based on these clinical guidelines;

5) taking into account the standards of medical care approved by the authorized Federal Executive Authority.

Primary specialized health care is provided by an oncologist, hematologist, or other specialist physicians at an outpatient hematology/oncology center, a primary hematology/oncology office, or the outpatient department of an oncological dispensary (oncological hospital).

When an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, family physicians, specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation at an outpatient hematology/oncology center, a primary hematology/oncology office, or the outpatient department of an oncological dispensary (oncological hospital) to receive primary specialized health care.

The consultation at the outpatient oncology center, primary oncology office, or outpatient department of an oncological dispensary (oncological hospital) must be conducted no later than 5 working days from the date of issuance of the referral. The oncologist at the outpatient oncology center (or, in the absence of such a center, the oncologist of the primary oncology office or outpatient department of the oncological dispensary/hospital, or the hematologist of the outpatient or inpatient hematology care unit) shall arrange for the acquisition of biopsy (surgical) material and coordinate other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic studies at a medical organization that includes an outpatient hematology/oncology care center (primary oncology office), the attending physician shall refer the patient to an oncological dispensary (oncology hospital) or a medical organization providing medical care to patients with oncological/hematological diseases.

The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).

The timeframes for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.

An oncological disease diagnosis is established by an oncologist, and in cases of malignant neoplasms of lymphoid, hematopoietic, and related tissues included in ICD-10 categories C81–C96 and D45–D47, D50–D76, it is also established by a hematologist.

The oncologist of the ambulatory cancer care center (primary oncology office) refers the patient to an oncological dispensary (cancer hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive authority (hereinafter referred to as a federal medical organization), to clarify the diagnosis (in case of the impossibility of establishing a diagnosis, including the extent of the oncological process and the stage of the disease), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

For oncological diseases included in ICD-10 categories C37, C38, C40–C41, C45–C49, C58, D39, C62, C69–C70, C72, C74, as well as corresponding International Classification of Diseases for Oncology (ICD-O) 3rd edition codes 8936, 906–909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, the oncologist of an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall, in order to determine treatment tactics, organize a consultation or a medical board (consilium), including via telemedicine technologies, at federal state budgetary institutions subordinate to the Russian Ministry of Health that provide medical care (hereinafter referred to for the purposes of this Procedure as national medical research centers).

In complex clinical cases, to clarify the diagnosis (in the event of the impossibility of establishing the diagnosis, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist shall arrange for the referral of:

- digital images obtained from pathomorphological studies, sent to the fourth-group pathologoanatomical bureau (department) (reference center) via information interaction, including the use of telemedicine technologies for remote interaction between medical personnel;

- digital images obtained from diagnostic radiology methods, sent to the remote diagnostic radiology consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical personnel;

- biopsy (surgical) material for repeat pathomorphological, immunohistochemical, and molecular genetic studies: to the fourth-group pathologoanatomical bureau (department) (reference center), as well as to molecular genetic laboratories for molecular genetic studies.

Treatment tactics are determined by a medical board consisting of oncologists, a radiotherapist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for treating malignant neoplasms, antineoplastic drug therapy, and radiotherapy (hereinafter referred to as the oncological board), including an oncological board conducted using telemedicine technologies, involving other specialist physicians if necessary, or by a hematologist, with a board convened and other specialist physicians involved if necessary. The decision of the medical board is formalized in a protocol, signed by the participants of the medical board, and entered into the patient's medical documentation.

Dispanserization (follow-up) by an oncologist or hematologist for a patient with a diagnosed oncological or hematological disease is established and carried out in accordance with the procedure for dispensary observation of adults with oncological or hematological diseases.

For registration purposes, information on a newly diagnosed case of an oncological or hematological disease shall be sent within 3 working days by the oncologist or hematologist of the medical organization where the respective diagnosis was established to the oncological dispensary or the organization of a subject of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms, including through the use of the Unified State Health Information System.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population with oncological diseases is provided on the basis of medical indications stipulated by the regulations on the organization of specialized, including high-tech, medical care.

Specialized medical care, with the exception of high-tech medical care, in medical organizations subordinate to federal executive authorities is provided based on the medical indications provided for in paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, provided in the appendix to the provision on organizing the provision of specialized, including high-tech, medical care.

Waiting times for the provision of specialized (excluding high-tech) medical care must not exceed the timeframes established in the program of state guarantees of free medical care for citizens, approved by the Government of the Russian Federation.

If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.

If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.

Palliative medical care for a patient with oncological diseases is provided in accordance with the provision on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, public associations, and other non-profit organizations operating in the field of health protection.

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

Indications for hospitalization in a medical organization in an emergency or urgent form are:

1) presence of complications of the oncological/hematological disease requiring specialized medical care in an emergency and urgent form;

2) presence of treatment complications (surgical intervention, radiotherapy, drug therapy, etc.) of the oncological/hematological disease.

Indications for planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-hospital setting;

2) the presence of indications for specialized antitumor treatment (surgical intervention, RT, including contact, EBRD and other types of RT, drug therapy, etc.) requiring monitoring in an inpatient or day hospital setting.

Indications for discharging a patient from a medical organization are:

1) completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in an inpatient or day hospital setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day hospital setting established by the multidisciplinary team of the medical organization providing cancer care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) in cases where the patient fails to follow prescriptions or the internal regulations of the healthcare institution, provided this does not threaten the patient's life or the health of others

4) the need to transfer the patient to another medical organization according to the relevant medical specialty profile.

The conclusion on the advisability of transferring the patient to a specialized medical organization is made following a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned, on the basis of these clinical guidelines, taking into account the standards of medical care approved by the authorized federal executive body.

Due to the fact that cancer-associated anemia is a complication of the oncological disease itself or the ongoing treatment of the oncological disease, its correction is carried out as part of the treatment of the underlying disease.

Indications for hospitalization in a medical organization:

1) blood hemoglobin below 70 g/L;

2) hematocrit below 30%;

3) clinical signs of hemic hypoxia (including when hemoglobin is above 70 g/L and hematocrit level is above 30%)

Indications for patient discharge from a medical organization:

1) resolution of anemia;

2) resolution of symptoms of hemic hypoxia.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Orlova Rashida Vakhidovna – MD, Professor, Head of the Department of Oncology, Faculty of Medicine, Saint Petersburg State University; Chief Specialist in Clinical Oncology, City Clinical Oncology Dispensary of Saint Petersburg; Board Member of the Russian Society of Clinical Oncology (RUSSCO); Member of the American Society of Clinical Oncology (ASCO); Member of the European Society for Medical Oncology (ESMO).

2. Gladkov Oleg Alexandrovich – MD, Honored Doctor of the Russian Federation, Director of Evimed LLC, Chelyabinsk.

3. Kutukova Svetlana Igorevna – MD, Oncologist at the Department of Antitumor Drug Therapy No. 10, City Clinical Oncology Dispensary of Saint Petersburg; Professor at the Department of Oral and Maxillofacial Surgery, Associate Professor at the Department of Oncology, Faculty of Postgraduate Education, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health; Member of the Russian Society of Clinical Oncology (RUSSCO); Member of the American Society of Clinical Oncology (ASCO), Member of the Russian Dental Association (RDA), Member of the Saint Petersburg Dental Association (SPbDA).

4. Kopp Mikhail Valerievich – MD, Professor, Reaviz Medical University; Member of the Russian Society of Clinical Oncology (RUSSCO); Member of the American Society of Clinical Oncology (ASCO); Member of the European Society for Medical Oncology (ESMO).

5. Koroleva Irina Albertovna – MD, Professor, Reaviz Medical University; Member of the Russian Society of Clinical Oncology (RUSSCO); Member of the American Society of Clinical Oncology (ASCO); Member of the European Society for Medical Oncology (ESMO).

6. Poddubnaya Irina Vladimirovna – MD, Professor, Academician of the Russian Academy of Sciences, Head of the Department of Oncology and Palliative Care named after Academician A.I. Savitsky, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation

7. Ponomarev Rodion Viktorovich, PhD, Head of the Sector for the Study of Non-Tumor Blood Diseases, Hematologist at the Department of Hematology and Chemotherapy of Orphan Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health

8. Al-Radi Lyubov Sattarovna, PhD, Senior Researcher at the Clinical Diagnostic Department of Hematology and Chemotherapy with Day Hospital, National Medical Research Center for Hematology ofрти the Russian Ministry of Health

9. Tatyana N. Moiseeva – Cand. of Med. Sci., Head of the Clinical and Diagnostic Department of Hematology and Chemotherapy with Day Patient Care, National Medical Research Center for Hematology of the Russian Ministry of Health

Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Oncologists 31.08.57

2. Hematologists 31.08.29

3. General Practitioners 31.08.49

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, provided there are justified additions/comments to the previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Table 1. Recommended doses of erythropoiesis-stimulating agents and principles of their adjustment in adult cancer patients receiving chemotherapy

¹ All erythropoietins are administered subcutaneously.

² Achievement of an Hb level of 120 g/L or an increase in Hb level by more than 20 g/L over 2 weeks.

Table 2. Recommended intravenous administration regimens for iron preparations

¹ Iron preparations must not be administered on the days of anti-tumor drug administration.

Table 3. Recommended vitamin administration regimens

Appendix B. Physician Action Algorithms

Figure 1. Recommended algorithm for evaluating a patient with anemia in malignant neoplasm.

Figure 2. Recommended algorithm for treating anemia in patients with malignant neoplasms.

Appendix C. Patient Information

Anemia is a frequent symptom of malignant neoplasms themselves, as well as a common complication of anti-tumor treatment (drug therapy and radiation therapy). The main cause of anemia in malignant neoplasms is the suppression of erythropoiesis and erythrocyte maturation processes in the patient's bone marrow, but anemia can also result from other causes (blood loss, erythrocyte destruction, etc.).

Anemia negatively impacts the patient's quality of life and the efficacy of anti-tumor treatment (due to the inability to administer cycles of drug therapy and radiation therapy at optimal doses and within optimal timeframes — when anemia develops, it becomes necessary to reduce the calculated drug dose and increase the interval between cycles of drug therapy and radiation therapy).

Among the main symptoms of anemia are pallor of the skin and mucous membranes, tachycardia, shortness of breath upon minor physical exertion and at rest, dizziness, tinnitus, a feeling of weakness, and increased fatigue, which worsen with physical exertion.

The main clinical and laboratory test for detecting anemia is the complete blood count, which evaluates blood hemoglobin levels and hematocrit.

Correction of anemia in malignant neoplasms can be performed via replacement blood transfusions — transfusion of red blood cell components, or through the use of medications: erythropoiesis-stimulating agents, iron preparations, etc. The choice of optimal treatment tactics is determined by the attending physician.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. ECOG/WHO Scale for assessing the general condition of the patient

Russian name: ECOG Performance Status Scale.

Original name (if any): The ECOG Scale of Performance Status.

Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655.

Type: rating scale.

Purpose: Assessment of the patient's general condition.

Notes: none.

Appendix G2. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 scale

Russian name: CTCAE toxicity scale

Original name (if any): Common Terminology Criteria for Adverse Events (CTCAE) v 5.0

Source: Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 Publish Date: November 27, 2017 (http://ctep.cancer.gov).

Type: rating scale.

Purpose: Assessment of adverse event severity