Case Study: Hb decline in patient with stage IIIc serous ovarian carcinoma

A 62-year-old woman with progressive abdominal distension and fatigue presented with recently developed nausea and vomiting. A physical examination of the patient revealed ascites. A computed tomography (CT) scan of the abdomen showed omental caking and a bulky adnexal mass, and confirmed the presence of ascites. Paracentesis confirmed adenocarcinoma consistent with a diagnosis of primary ovarian cancer. At presentation, the patient's hemoglobin (Hb) level was 9.5 g/dL. Esophagogastroduodenoscopy showed that the patient has a benign ulcer at the gastroesophageal junction, and a colonoscopy showed extensive diverticular disease.

A diagnosis of stage IIIc serous ovarian carcinoma was made and the patient underwent debulking surgery. She received two units of blood at the time of surgery. She was assigned to undergo follow-up treatment with combination carboplatin and paclitaxel on post-op day 6 prior to discharge from the hospital. Hb level at discharge was 10.8 g/dL.

Ten days later, the patient returned for a follow-up Hb nadir check. At this time, her Hb was 8.5 g/dL.

Upon initial examination of this case, what should be the greatest concern for this patient? Why?

Lee Schwartzberg, MD: With no intervention over a 10-day period, this patient's Hb level decreased more than 2 g/dL. That is definitely a concern because it represents a significant drop in Hb.¹ It establishes a trajectory that is of concern in terms of developing worsening anemia at a rapid rate.

Lawrence Goodnough, MD: Agreed. The major concern here is the possibility that this patient will require further red blood cell (RBC) transfusions.

Based on this patient's clinical scenario, what type of anemia may be present and why?

Goodnough: This patient's decline in Hb may reflect a variety of types of anemia (eg, blood loss related to cancer, gastrointestinal (GI) ulcer or diverticulosis, impaired erythropoiesis due to vitamin or mineral deficiency or chemotherapy, or drug-induced erythrocyte destruction.^2-5 Because the patient has undergone chemotherapy with carboplatin, there is the possibility that she is suffering from chemotherapy-induced anemia (CIA). It has been reported that approximately 50% of patients treated with platinum-based chemotherapy develop CIA.⁶ It is also possible that the cancer itself is causing the anemia¡ªie, anemia of cancer. Finally, the patient may have impaired renal function and an erythropoietin-deficient anemia.^1,7

It is most likely that the anemia is in fact multifactorial, with several of these conditions contributing to the anemia.

Schwartzberg: The etiology of the anemia is not immediately clear; therefore, as Dr. Goodnough described, a differential diagnosis of the anemia is warranted. The patient has an ulcer and diverticulosis, which can lead to both acute and chronic GI blood loss-related anemia.^3,4 Acute blood loss would definitely be suspect here because of the rapid Hb drop that occurred in 10 days. However, chronic blood loss is also a concern because it leads to iron deficiency anemia.^3,8 Both types of blood loss should be considered and evaluated.

Further analysis of the data demonstrates that the patient's initial Hb level was 9.5 g/dL. She was transfused two units of blood and had reasonable response to this intervention. This would indicate that the problem is not necessarily acute and continuing blood loss, but may be subacute blood loss.

In addition, the patient underwent surgery and may have sustained blood loss intraoperatively. Blood drawing at the hospital, which is a frequent cause of anemia,⁹ could also be the problem in this patient.

As Dr. Goodnough pointed out, another etiology to consider would be anemia of cancer. The patient has ovarian cancer, which is fairly extensive as evident by the presence of ascites. The malignant state can negatively affect production of RBCs through various mechanisms, including infiltration and replacement of the bone marrow with tumor cells or suppression of RBC production due to inflammatory processes. Cancer can impede erythropoiesis by producing inflammatory cytokines, which can result in shortened RBC survival, impaired iron metabolism, and insufficient differentiation and proliferation of erythroid progenitor cells. Malignancy also interferes with iron absorption and processing, resulting in iron deficiency anemia.¹⁰ Of course, the use of chemotherapeutic agents is damaging to the bone marrow and RBCs as well.1

Nutritional anemia should also be considered in the differential diagnosis.¹ Patients with cancer often have a diminished nutritional state due to general malnutrition, loss of appetite, or malabsorption in the intestinal tract.^1,2,10 Given the combination of an ulcer and malignancy, the patient may have an underlying malabsorptive state. Depending on the type of disease in the stomach, the patient may lack intrinsic factor leading to vitamin B12 malabsorption, or perhaps atrophy of the acid-producing cells resulting in iron malabsorption.^1,11 Other types of disorders, such as malignant involvement of the intestinal tract, can lead to a folate deficiency as well.¹² There are other etiologies to consider. Further workup would include an evaluation of the complete blood cell count (CBC) and peripheral smear.¹

What are the risk factors for severe anemia in this patient and what further information is relevant in the patient's history?

Schwartzberg: In general, risk factors for developing anemia include poor nutritional status, advanced age, comorbid cardiac disease, poor functional status, prior weight loss and low Hb at baseline or prior transfusion history.^1,13-15 Specific factors relating to the malignancy include metastatic disease to two or more sites and prior radiation therapy to more than 20% of the body.¹⁴

Unfortunately, this patient has several risk factors for anemia, including the malignancy itself, the ulcer, and the hospitalization and surgery.^1,4,9,12,13 The only general risk factor for developing anemia that the patient presents with is a preexisting anemia. Obtaining further information about possible prior treatments for anemia will provide further insight into the current anemia.

The first aspect to investigate is the patient's prior history of anemia. Prior information will allow the health care provider to determine the acuity and severity of onset as well as the possibility of a long-standing anemia that may be due to familial types of anemia. This would be of value in determining whether to further investigate the possibilities of underlying hemoglobinopathies.¹

Other contributory comorbidities may include chronic liver disease or diabetes, neither of which appears to be relevant in this patient, or chronic kidney disease.^13,16

Nutritional history is also important when evaluating people for anemia. For example, vegans may not have enough iron in their diet.¹⁷ Furthermore, some drugs can cause an immune-related hemolytic anemia,³ while others can even cause aplastic anemia; thus, awareness of a patient's medication history is also important.⁶

Goodnough: Furthermore, at 62 years of age, this woman is undoubtedly postmenopausal. In women who are not postmenopausal, the risk of iron deficiency anemia can be high because of erythrocytes lost during menstruation.⁸ Asking about the duration and heaviness of menstrual flow may help identify this risk.

In this patient's case, an upper GI ulcer and lower GI diverticula also are risk factors for blood loss leading to anemia.

It is advisable to ask the patient about her alcohol intake. Alcohol, and possibly its metabolite, acetaldehyde, have been reported to directly suppress hematopoiesis.¹²

Approximately 20% of people in industrialized countries are deficient in vitamin B12,¹⁸ whereas following the introduction of folate fortified foods in the United States, folate deficiency was reduced from 20% to 1%.¹¹ Importantly, both folate and vitamin B12 are needed for erythropoiesis.¹⁹ Because patients with cancer may neglect nutrition, ask about dietary intake of meat, salmon, eggs, dairy products, and vitamin B12-fortified cereals to evaluate diet status. Serum cobalamin and homocysteine levels may be needed to identify patients who have adequate intake but are not processing vitamin B12.¹⁸

When patients are receiving chemotherapy, can it be assumed that the Hb decline is related to CIA, or is further investigation warranted regarding the etiology of the anemia?

Goodnough: Any patient whose Hb level is less than 11 g/dL should be evaluated.¹ Although a sudden, significant drop in Hb may signal blood loss, the rate of decline of Hb level is not generally diagnostic. The rate of decline, however, may affect the pace of workup and management decisions.

Schwartzberg: For me, the pattern of change in Hb values is important to the determination of the etiology and the need for further investigation. For patients in whom initial Hb and other hematologic parameters are normal but subsequently develop the typical pattern of CIA that is temporally related to the administration of chemotherapy, it can be safely considered to be CIA. However, the health care provider should still assess the iron, vitamin B12, and folate stores if indicated, to be certain that the patient has adequate stores for erythropoiesis. Yet for patients presenting with established anemia, or those whose change in Hb is more exaggerated than would be expected from CIA alone, the health care provider should assess for other contributing causes.¹

It is also important to note that CIA can have a relatively quick onset. The European Cancer Anaemia Survey (ECAS), a large, prospective, epidemiologic, observational survey of 15,367 patients in 24 countries in Europe, aimed to assess the prevalence and incidence of anemia in cancer patients. The patients included those with solid or hematologic tumors regardless of disease status or cancer treatment who had no anemia at enrollment, no anemia treatment, and first chemotherapy during the study for at least two cycles. 20 Anemia was defined as Hb < 12.0 g/dL based on toxicity-grading criteria from the National Cancer Institute and the European Organization for Research and Treatment of Cancer. Of 1,821 patients included in the chemotherapy incidence population who began chemotherapy with Hb ¡Ý 12 g/dL with complete values, 62% of patients experienced an Hb decline by 1.5 g/dL within a median time of 6.1 to 7.2 weeks; 51% experienced an Hb decline by 2 g/dL within a median time of 7.3 to 8.9 weeks.20 However, the onset of acute bleeding or hemolysis, for example, is more rapid and would direct the health care provider to investigate other causes for the anemia.

In general, the common causes of anemia should be evaluated before attributing anemia to chemotherapy. Therefore, it is worthwhile to obtain routine vitamin B12, folic acid, ferritin, iron and total iron-binding capacity tests in virtually all patients. A Coombs test, haptoglobin test, and reticulocyte counts should also be considered if there is a suspicion of a hemolytic component.¹

Goodnough: In addition, abnormal paleness, dark urine, yellowing of skin or tachycardia detected on physical exam could be an indication of hemolytic anemia.^13,21 A change in the color of stool might suggest anemia due to GI bleed, which could be investigated with a simple guaiac test.^1,13 Mucositis of the mouth or a glossitis (an inflammation of the tongue), or posterior column sensory loss might indicate vitamin B12 or folate deficiency.¹¹ Iron deficiency could be reflected by symptoms such as brittle fingers nails, or pica, a craving for ice or clay.⁸ These can be used to further guide the workup.

When analyzing a CBC, what parameters provide further guidance in determining the etiology of the anemia?

Schwartzberg: First, health care providers should assess the entire CBC for its various components.¹ In the absence of a pancytopenia, the etiology is less likely to be an underlying bone marrow disorder. However, if the white cells, red cells, and platelets are abnormal, then the patient has pancytopenia, and the physician should consider a chemotherapy effect diffusely involving the bone marrow production of blood cells across all the compartments of blood cells, bone marrow infiltration of cancer cells, or an intrinsic bone marrow problem such as myelodysplasia.³

Another assessment of the CBC is the mean corpuscular volume (MCV). The size of the RBC gives important information regarding the etiology. Using the MCV, anemias can be separated into three categories: microcytic, normocytic, or macrocytic. There are different etiologies for anemia depending on whether a patient is microcytic, normocytic, or macrocytic. The number of reticulocytes also gives information regarding the rapidity with which the bone marrow is releasing RBCs.¹

Goodnough: A CBC and a peripheral blood smear can both provide clues to narrow the cause of the anemia.¹ For example, spherocytes on the smear would suggest that the patient has hemolysis.¹⁶ For megaloblastic anemia, such as those arising from vitamin B12 or folate deficiencies, look for hypersegmentation of the neutrophils and macrocytic RBCs.¹¹

Red cell indices can help distinguish various types of anemia such as¹:

• Iron deficiency anemia is typically hypochromic, microcytic¹³
• Vitamin B12 and folate deficiency is normochromic, macrocytic²²
• Anemia due to blood loss is normochromic, normocytic²²

With cancer-related anemia, you would see either normocytic normochromic, or normal, cells. The reticulocyte count is also usually low. Interestingly, once chemotherapy is added in to the mix, macrocytosis is more typical. Schistocytes can be seen and may indicate hemolysis. Tumor invasion of the venous system can produce red cell shearing and hemolysis. In the bone marrow, cellularity is usually quite normal. The finding of iron-laden macrophages may indicate interference with hematopoesis.¹² The finding of tear drop red cells, nucleated red cells or a shift to immaturity of the white cells (leukoerythroblastic changes) may be indicative of a myelophthistic picture or tumor invasion of the marrow.^3,12

What exam findings would contribute to narrowing the cause of anemia?

Schwartzberg: Only a few exam findings would help narrow the cause of anemia. Generally, further laboratory testing is needed.

An enlarged spleen should lead a health care provider to suspect anemia secondary to either a primary hematologic disorder such as myeloproliferative disorder, myelofibrosis, and occasionally myelodysplastic syndrome.^12,23,24

There are some physical findings that relate to specific anemias. Patients who have iron deficiency anemia often have cheilosis or crusting of the furrows in the mouth. Patients can also have a smooth tongue.¹² In advanced cases of vitamin B12 deficiency, patients may have neurologic deficiencies such as loss of vibratory sense or position sense,^11,12 but these are very late findings and it would be unlikely to manifest in this particular patient. Rarely, myelophthisic processes can be present, where infection or tumor invades the bone marrow.³ Fever or other symptoms indicative of a chronic inflammatory state that could also reduce RBC production should be evaluated.

Goodnough: Physicians should look for the following symptoms or signs of anemia that reflect the effect of decreased oxygen transport on various systems when physiologic mechanisms fail to adequately compensate ¹⁰:

• Cardiorespiratory system

• Tachycardia, palpitations
• Exertional dyspnea
• Increased pulse pressure, systolic ejection murmur
• Cardiac enlargement, eccentric hypertrophy

• Vascular system

• Pale skin, mucous membranes, and conjunctiva
• Low skin temperature

• Central nervous system

• Fatigue
• Dizziness, vertigo
• Depressed mood
• Impaired cognitive function

• GI system

• Anorexia
• Nausea

• Genital tract

• Menstrual problems
• Loss of libido

• Immune system

• Impaired T-cell and microphage function

Anemia-induced fatigue is common in patients with cancer. Nevertheless, a complete workup to detect any other possible causes of fatigue and to identify the specific type of anemia is essential.^1,25

Are oncology patients frequently iron deficient? Vitamin B12 deficient? Folate deficient?

Goodnough: Oncologists are most likely to see iron deficiency in women who have not experienced menopause.⁸ As patients age, loss of intrinsic factor can lead to vitamin B12 deficiency and therefore it may be more common in middle-aged or elderly patients.²⁶ Folate deficiency would be found in alcoholics while iron or other nutritional deficiencies may occur in people who do not maintain good diets.^16,27

For the elderly, both men and women are at risk for iron deficiency due to diet, use of NSAIDs, gastrointestinal pathology, such as Helicobacter pylori infection or undiagnosed polyps, or colon cancer.^5,8,28

Schwartzberg: Agreed. It is important to remember that as the bone marrow is being asked to produce more and more cells, maintaining proper precursor stores is vital.¹³

Please discuss how you would proceed to diagnose the patient. What tests do you recommend ordering and/or examinations to perform, etc.?

Schwartzberg: I would look at the Complete Blood Count and review the peripheral blood smear under the microscope. I would evaluate the patient for underlying nutritional causes of anemia, including vitamin B12, folate and iron deficiencies. It would be helpful to obtain older health records to see if the patient has a long standing history of anemia. I would consider evaluating for a hemolytic process with haptoglobin and Coombs test and would certainly obtain a reticulocyte count to assess the bone marrow's ability to produce new red blood cells. Finally, I would monitor frequently for occult blood loss given the finding of an ulcer in the gastrointestinal tract that could intermittently bleed and contribute substantially to ongoing anemia.¹

Goodnough: I would recommend performing the following tests:

• Serum iron, total iron-binding capacity (TIBC), percentage of saturation¹
• Serum ferritin¹
• Reticulocyte count¹
• Creatinine, ESTGFR (glomelular filtration rate) (if not already obtained)^1,13

References

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