This month, Jeffrey A. Gilreath, PharmD, and George M. Rodgers, MD, PhD, review common and complex scenarios in the management of anemic patients with cancer.
This material is repurposed from “How I treat cancer-associated anemia,” published in the August 13, 2020 edition of Blood.
Diagnosis and Management of Cancer-Associated Anemia
Despite increasing use of targeted cancer treatments, such as tyrosine kinase inhibitors, monoclonal antibodies, and immunomodulating agents, cancer-associated anemia remains a common clinical problem. The prevalence of anemia can exceed 90% for patients receiving certain treatments.
- Cancer-associated anemia is caused by one or more of three primary mechanisms: ineffective erythropoiesis, hemolysis, or blood loss.
- Variables such as sex, age, cancer subtype and stage, and type of treatment may all contribute to the risk of cancer-associated anemia. Identifying specific causes of cancer-associated anemia is necessary for developing effective treatment strategies.
- The route chosen for iron repletion (oral vs. IV) depends upon the onset and grade of cancer-associated anemia, the degree of iron insufficiency, the likelihood of oral absorption, the presence of gastrointestinal comorbidities, and the potential for drug-drug interactions.
- ESAs should be reserved for patients who require frequent RBC transfusions.
- RBC transfusion remains an option for treating grades 2-4 cancer-associated anemia when other therapies fail.
Variables such as sex, age, cancer type, stage, and type of treatment, as well as concomitant medications and comorbidities, may all contribute to cancer-associated anemia, which makes broad treatment recommendations difficult. Identifying specific causes of cancer-associated anemia is necessary for developing effective treatment strategies.
Goals of Therapy for Cancer-Associated Anemia
Cancer-associated anemia is caused by one or more of three primary mechanisms: ineffective erythropoiesis, hemolysis, or blood loss. Our approach, illustrated in the FIGURE, subclassifies potential causes of cancer-associated anemia by first listing three broad categories: production, destruction, and blood loss. Further subgrouping creates three additional categories: drug-induced, infectious-related, or other causes.
The short-term goal of treatment is correcting the quantitative deficits of hemoglobin (Hb) and erythrocytes to meet the oxygenation requirements of all tissues. If successful, meeting these goals also can translate into increased quality of life (QoL) through improvement in cognition, fatigue, and exercise tolerance.
Depending upon cancer stage and prognosis, goals may shift from correction of cancer-associated anemia to maintaining QoL by preventing worsening anemia and dependency on red blood cell (RBC) transfusion.
Currently available treatments focus on increasing RBC production to counterbalance cancer treatment–induced effects on production. Particular attention is paid to RBC destruction and blood loss because they can often be addressed by targeting the underlying disease or screening for concomitant medications that are exacerbating blood loss.
Oral Versus IV Iron
For patients in whom iron deficiency is a contributing factor to cancer-associated anemia, the route chosen for iron repletion (oral vs. intravenous [IV]) depends upon the onset and grade of cancer-associated anemia, the degree of iron insufficiency, the likelihood of oral absorption, the presence of gastrointestinal comorbidities, and the potential for drug-drug interactions.
A 58-year-old man presenting with intermittent hematochezia is diagnosed with low-risk stage III adenocarcinoma of the colon. He receives adjuvant therapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) every 14 days for 6 months. His tumor is considered curable. Baseline laboratory results show that Hb was 11.6 g/dL, and results from iron studies showed ferritin 9 ng/mL, serum iron 41 mg/dL, total iron binding capacity 438 mg/dL, and transferrin saturation (TSAT) 9%. How should this patient’s anemia be treated?
Case 1 Commentary
In the face of ongoing blood loss and absolute iron-deficiency anemia (AIDA), IV iron is the preferred method of correction. Our three favored products are low molecular weight (LMW) iron dextran (500-2,000 mg/dose), ferric carboxymaltose (FCM; 750 mg/dose), and iron sucrose (200-300 mg/dose), because these products have been extensively studied in patients with cancer. Also, LMW iron dextran and FCM can be given in larger doses to correct AIDA in the shortest timeframe.
Depending upon patient weight, iron doses of 1,000 to 1,500 mg replenish body stores, and often increase Hb by 2 to 3 g/dL in the absence of ongoing blood loss. We minimize and, when possible, synchronize blood draws to avoid iatrogenic anemia.
Adverse events associated with IV iron products include infusion reactions, but this is less of a concern with newer agents, which have minor infusion reaction rates of ~1 per 200 infusions and major infusion reaction rates of ~1 per 200,000 infusions.
Mild reactions are treated by stopping the infusion and resuming it at a lower infusion rate; moderate to severe reactions are treated by stopping the infusion, treating with IV fluids and corticosteroids, and escalating care, as needed.
We monitor monthly complete blood counts and iron studies (ferritin and TSAT) following IV iron administration. If FCM is used, phosphate levels are monitored. Hypophosphatemia typically resolves within 3 to 6 weeks. We repeat IV iron treatment if AIDA returns or if the ferritin plateaus and declines to <100 ng/mL and TSAT remains <20%.
The treatment of cancer-associated anemia with erythropoiesis-stimulating agents (ESAs) began in the 1990s. ESAs reduce RBC transfusions; in some cases, ESA dosing may be lowered by the addition of IV iron.
A 76-year-old man with a history of autoimmune disease is newly diagnosed with metastatic non–small cell lung cancer. Baseline iron studies showed serum ferritin of 535 ng/mL and TSAT of 23%. He began receiving carboplatin plus paclitaxel once every 3 weeks. After 2 cycles, his Hb level decreased from 12.2 g/dL to 9.9 g/dL. Reticulocyte hemoglobin content is within normal limits, and reticulocytes are inappropriately low for the degree of anemia. After 2 more cycles, his Hb level declines to 7.4 g/dL and the patient receives a 2-unit RBC transfusion. How should this patient’s anemia be treated?
Case 2 Commentary
Because the risks of ESAs (including venous thromboembolism) can potentially decrease cancer patient survival, we reserve their use for patients with nonmyeloid malignancies who are iron replete or iron-refractory and have anemia that requires frequent transfusions with packed RBCs, or for patients with decreased QoL undergoing palliative myelosuppressive cancer treatment.
To prevent unnecessary clinic visits, and when payers permit it, we obtain ESAs for home use (prefilled syringes available in fixed doses). When payers require them, biosimilar agents are acceptable.
For ESA monitoring and dosage modifications, we refer the reader to the American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update on management of cancer-associated anemia with ESAs.
An FDA-mandated Risk Evaluation and Mitigation Strategies program for ESAs was ended in 2017; however, recent additions to ESA drug labels state that ESAs are “not indicated for patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.” Literal interpretation of this update seemingly disqualifies most patients from receiving ESA therapy, including the patient described in case 2.
However, after informing this patient of the benefits and risks, as well as the signs and symptoms of VTE, our preference is to offer ESA therapy to minimize transfusions and potentially improve his QoL.
Red Blood Cell Transfusions
RBC transfusions in patients with cancer have been linked to an increased risk of thrombosis, cancer recurrence, and decreased survival. Other known risks include pathogen transmission, transfusion reactions, iron or volume overload, and alloimmunization.
RBC transfusions also are associated with a 10-fold greater risk of major morbidity than IV iron (1 in 21,413 for RBCs vs. >1 in 200,000 for current IV iron products). Thus, it is ultimately up to the clinician to consider clinical indicators that show a need for transfusion rather than laboratory abnormalities alone.
Although each unit of packed RBCs contains ~250 mg of iron, that iron is not immediately bioavailable because transfused RBCs live for roughly 90 days. RBC transfusion, which takes approximately 1 to 2 hours per unit to administer, remains an option for treating grades 2 to 4 cancer-associated anemia when other therapies fail, but it may be refused by those with religious proscriptions. In these instances, ESAs may be offered.
An 82-year-old man with diabetes presents with weight loss, dyspnea, and anemia. He is diagnosed with prostate cancer metastatic to the bone and lung; after androgen deprivation therapy fails, he is deemed castrate-refractory and is offered enzalutamide, an androgen receptor inhibitor. Laboratory results showed Hb 10.1 g/dL, hematocrit 28%, mean corpuscular volume 81 fL, and platelet count 122×109/L; iron studies showed ferritin 592 ng/mL and TSAT 18%. Serum creatinine was 1.2 mg/dL, and his weight was 73 kg.
Case 3 Commentary
Patients receiving therapy aimed at continually suppressing cancer growth such as antihormonal agents or tyrosine kinase inhibitors may experience cancer-associated anemia indefinitely.
Ferritin is often elevated in cases like this one, because of widespread cancer and inflammation. The borderline low TSAT indicates functional iron-deficiency anemia. Cancer-associated anemia can be especially difficult to address when Hb levels are between 10.1 and 11.9 g/dL, a condition not low enough to use packed RBCs and not severe enough to qualify for ESA therapy. Moreover, ESAs are not indicated for patients with cancer who are receiving hormonal therapy.
Myelosuppressive chemotherapy is the only treatment that qualifies a patient for an ESA; all other anemias must be considered cancer-associated anemia and treated by other means, such as IV iron monotherapy or transfusion when indicated. Enzalutamide does not constitute myelosuppressive chemotherapy; therefore, using ESAs under this setting is contraindicated.
If hormonal therapy fails and myelosuppressive chemotherapy is considered, ESA use would then become an option.
Several therapies could prove useful in the treatment of cancer-associated anemia, but have not been extensively studied in this setting. These include ascorbic acid, roxadustat, luspatercept, and hepcidin antagonists.
Given the intricate mechanisms driving cancer-associated anemia, no single drug will be both safe and effective for all patients. Clinical trials aimed at correcting cancer-associated anemia should enroll patients with similar underlying comorbidities and concomitant medications to better define populations likely to benefit from a single intervention.