Iron deficiency anemia is a common complication of cancer and cancer treatments. Anemia occurs when there are not enough healthy red blood cells to carry oxygen to tissues throughout the body. Red blood cells contain hemoglobin, which binds to oxygen and transports it. Iron is an essential component of hemoglobin. When the body does not have enough iron to make hemoglobin, anemia develops. There are several mechanisms by which cancers can lead to iron deficiency and anemia. Identifying and treating the underlying cause of iron deficiency is important for improving quality of life and outcomes in cancer patients.
Cancers that Cause Chronic Blood Loss
One of the most common ways cancers cause iron deficiency anemia is through chronic blood loss from the site of the tumor. Any cancer that causes bleeding can lead to iron deficiency over time as iron stores become depleted. Common cancers that are associated with iron deficiency anemia due to chronic blood loss include:
Colorectal Cancer
Colorectal cancer, or cancer of the colon or rectum, often causes slow bleeding from the large intestine. This chronic blood loss leads to iron deficiency anemia in around 20-30% of people with colorectal cancer. The anemia tends to develop slowly over time and is sometimes one of the initial symptoms that prompts further testing and diagnosis of colorectal cancer.
Stomach Cancer
Stomach cancer can also cause slow chronic bleeding into the stomach and loss of iron. Almost a third of people with stomach cancer will develop iron deficiency anemia during the course of their disease. The tumor may erode into stomach blood vessels or the bleeding may come from the tumor itself.
Esophageal Cancer
Esophageal cancer arises in the tube that carries food from the throat to the stomach. The tumor can bleed directly into the esophagus, leading to iron deficiency anemia in up to a quarter of patients.
Lung Cancer
While lung cancer does not directly cause gastrointestinal bleeding, it can lead to iron deficiency anemia in about 20% of people. Coughing up blood (hemoptysis) from lung tumors that erode into blood vessels is one cause. Large lung cancers may also impair production of erythropoietin, the hormone that stimulates red blood cell production in the bone marrow.
Gynecologic Cancers
Cancers of the uterus, cervix, ovaries, and vulva account for about 10% of cancer-related iron deficiency. These tumors can chronically bleed, leading to anemia. Ovarian cancer does not always have obvious bleeding, but can still disrupt iron homeostasis.
Bladder Cancer
Bladder cancer is another tumor that can cause chronic blood loss from the urinary tract, resulting in iron deficiency anemia in around 10-20% of patients. Blood in the urine (hematuria) is a common early sign of bladder cancer.
Kidney Cancer
Kidney cancer may also lead to blood in the urine. Additionally, paraneoplastic syndromes from kidney cancer can cause anemia through other mechanisms such as impairing erythropoietin production.
Prostate Cancer
Advanced prostate cancer that has spread beyond the prostate gland itself can invade into blood vessels causing bleeding that leads to anemia in about 10% of patients.
Head and Neck Cancers
Certain cancers of the head and neck area like nasal cavity, nasopharynx, mouth, and throat cancers bleed chronically in 10-15% of cases. Surface ulcers and erosion into blood vessels contributes to blood loss.
Cancers that Invade Bone Marrow
The bone marrow is where red blood cells are produced by hematopoietic stem cells. When cancer spreads to the bone marrow, it can disrupt normal blood cell production and lead to anemia.
Leukemias
Leukemia arises from the bone marrow and crowds out the normal development of red blood cells, white blood cells, and platelets. Anemia from low red blood cell count is one of the hallmarks of leukemia. Both acute and chronic leukemias profoundly impair red blood cell production.
Lymphomas
Lymphomas are cancers of white blood cells called lymphocytes. Just as leukemia invades the bone marrow, lymphomas can also spread to the marrow. They suppress normal development of other blood cell lines, resulting in anemia in 40-60% of lymphoma patients.
Multiple Myeloma
Multiple myeloma is a cancer of plasma cells, another type of white blood cell in the bone marrow. It causes anemia through infiltration and replacement of the marrow space, impairing production of both red blood cells and their oxygen carrying capacity.
Metastatic Solid Tumors
While cancers like breast, prostate, and lung cancer arise in specific organs, they can spread or metastasize to the bone marrow as they advance. Displacement of the bone marrow is another way these solid tumors can lead to cancer-related anemia.
Cancers that Impair Iron Utilization
There are also some cancers that can cause anemia through mechanisms other than blood loss or impaired production. These include cancers that affect the body’s ability to use and store iron obtained from the diet.
Multiple Myeloma
In addition to replacing bone marrow, multiple myeloma causes anemia by releasing a cytokine called interleukin-6. This cytokine causes inflammation and impairs the ability of iron to be released from storage sites. The iron becomes “locked away” and unavailable for making hemoglobin and red blood cells.
Chronic Lymphocytic Leukemia
This type of leukemia involves clonal expansion of abnormal lymphocytes. These leukemic cells produce hepcidin, an inflammatory mediator that prevents iron release and recycling. The resulting iron restricted erythropoiesis contributes to anemia.
Renal Cell Carcinoma
This type of kidney cancer can produce paraneoplastic syndromes that result in anemia through several mechanisms. Tumor necrosis factor alpha and hepcidin production contribute to iron deficiency by blocking its release from intestinal cells and hepatocytes. Renal cell carcinoma is also associated with abnormally low levels of erythropoietin.
Cancers that Cause Anemia of Inflammation
Many cancers spur the immune system to release inflammatory cytokines. These pro-inflammatory signals can disrupt iron homeostasis and `trap` iron in storage sites like the liver and spleen. This contributes to an anemia not primarily of iron deficiency, but rather an anemia caused by inflammation. Key inflammatory cytokines linked to this process include:
Tumor Necrosis Factor Alpha
Produced by immune cells and cancer cells themselves, TNF-alpha is a potent mediator of inflammatory anemia. It decreases the production of erythropoietin and shifts iron into storage.
Interleukin-1 and Interleukin-6
These pro-inflammatory cytokines have similar effects of trapping iron in macrophages and hepatocytes and limiting its availability for heme synthesis. Their levels correlate with the severity of anemia of inflammation.
Some cancers associated with high rates of anemia of inflammation include:
– Multiple myeloma
– Non-Hodgkin lymphoma
– Lung cancer
– Breast cancer
– Ovarian cancer
– Pancreatic cancer
Identifying the involvement of inflammatory cytokines can help guide treatment to alleviate cancer-related anemia.
Cancers that Cause Hemolysis
Hemolysis is the excessive destruction of red blood cells. It leads to anemia both from the loss of red blood cells and the hemoglobin they contain. Some cancers can cause your immune system to attack and destroy your body’s own red cells. Cancers associated with hemolytic anemia include:
Chronic Lymphocytic Leukemia
This leukemia can trigger production of autoantibodies that mark red blood cells for removal by the spleen and liver. Complement proteins that poke holes in red blood cells can also be activated.
Lymphomas
Lymphomas, especially Hodgkin lymphoma, are another source of autoantibodies that can cause immune hemolysis. They may also impair complement regulation.
Multiple Myeloma
Paraneoplastic effects from myeloma proteins include interference with red blood cell membranes that promotes hemolysis.
Identifying autoantibodies and signs of complement activation are important to diagnose and treat the hemolytic component of anemia. This helps minimize the destruction of precious remaining red blood cells in cancer patients.
Cancer Treatments that Cause Anemia
Certain cancer treatment regimens are also associated with increased risk of iron deficiency and other forms of anemia. Being aware of these drug effects helps monitor for and manage treatment-related anemia.
Platinum Chemotherapy Drugs
Platinum agents like cisplatin and carboplatin are broad anti-cancer chemotherapy drugs. A side effect seen in over two-thirds of patients is anemia, usually 1-2 months after starting treatment. They likely suppress natural erythropoietin production.
Alkylating Chemotherapy Agents
Alkylators are another class of chemo drug used in many protocols. Examples include cyclophosphamide, ifosfamide, dacarbazine, and temozolomide. Up to half of patients develop anemia during treatment through direct bone marrow toxicity.
Antimetabolite Chemotherapy Drugs
Antimetabolites like 5-fluorouracil, cytarabine, and methotrexate interfere with DNA synthesis to block cancer cell growth. About 40% of people develop anemia, especially after prolonged use.
Targeted Therapy Kinase Inhibitors
Newer targeted cancer drugs like imatinib, sorafenib, and sunitinib inhibit specific growth signaling pathways. Over a third of patients develop anemia, sometimes severe. The mechanisms may involve impaired iron utilization and erythropoietin suppression.
Angiogenesis Inhibitors
Anti-angiogenic drugs like bevacizumab inhibit growth of new blood vessels that feed tumors. They can suppress erythropoietin and exacerbate cancer anemia. Up to almost two-thirds of patients develop anemia with these drugs.
Radiation Therapy
Radiation aimed at tumors in the pelvis, abdomen, chest or head and neck often involve exposure of bone marrow. This can lead to radiation-induced damage to blood cell progenitors. Anemia develops in 20-40% of patients after substantial or whole body radiation therapy.
Surgery
Surgical procedures to remove tumors can result in acute blood loss during the operation. Chronic iron deficiency can also develop after procedures that affect the GI tract. For example, gastrectomy for stomach cancer impairs iron absorption long-term.
Conclusion
Iron deficiency anemia is a common complication across many different cancer types and treatments. The specific mechanism varies and includes chronic blood loss from tumors, marrow infiltration by cancer cells, impaired iron recycling and utilization, inflammation, hemolysis, and effects of treatments like chemotherapy, radiation, and surgery.
Identifying the primary drivers of anemia guides appropriate treatment. Intravenous iron supplementation replenishes iron stores depleted by blood loss and poor intake. Erythropoiesis stimulating agents like erythropoietin help counter chemotherapy and cytokine effects on red blood cell production. Managing inflammation and avoiding immune hemolysis can also improve anemia.
Often a combination of treatments are needed. Correcting cancer-related anemia is an important part of supportive care to improve cancer symptoms and quality of life. It helps restore energy and stamina for daily activities and ability to withstand cancer treatments. Overcoming cancer-related iron deficiency anemia requires understanding its multifaceted causes. With careful monitoring and targeted interventions, anemia can often be effectively managed.
