Discussing Cancer-Related Fatigue and Anemia with Patients

Fatigue and anemia often go hand-in-hand in patients with cancer. In fact, anemia is frequently a cause of fatigue. Both conditions may result from the cancer itself, from treatment, or from underlying causes. The incidence of each varies according to malignancy type and treatment, but it is impossible to predict who will develop fatigue or anemia. It is safe to say that most patients with cancer experience anemia and/or fatigue at some point during the course of their disease. The failure to treat these conditions can have a serious impact on a patient’s quality of life and survival outcome, particularly if they have an unidentified underlying cause.

What is Cancer-Related Fatigue?

At the 7th International Symposium on Supportive Care in Oncology, Lowell Anthony, MD, professor of medicine, LSUHSC, New Orleans, Louisiana, said, “Fatigue is something [healthcare providers] get tired of hearing about, because it is the most common symptom patients complain about.” It is not clear how many patients experience cancer-related fatigue (CRF); according to Dy et al (Journal of Clinical Oncology, 2008), “approximately 75% of patients with solid malignancies and 80% to 90% of patients undergoing chemotherapy or radiotherapy report fatigue at some point.”

CRF goes Beyond Mere Tiredness. The National Comprehensive Cancer Network (NCCN) practice guidelines on CRF define it as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”

The etiology of CRF is unclear, and Dr Anthony said it was a “highly complex” puzzle. There are many hypotheses, such as serotonin dysregulation or cytokine mediation. Recovery from surgery can trigger CRF. Several studies have established conclusively that CRF is not preceded by vigorous exercise and it is not improved with sleep.

Treatment-related CRF. Patients may experience CRF before, during, and after treatment; it might last a few days or persist for months. Some treatments reduce red blood cell production, resulting in anemia. Others cause nausea and vomiting, compromising the patient’s nutritional intake. Before initiating therapy, advise patients that treatment-related fatigue is common and does not necessarily mean their cancer is progressing.

CRF often sets in a few days to a few weeks after chemotherapy. Although any chemotherapy drug can lead to CRF, patients receiving vincristine (On-covin), vinblastine (Velbe), and cisplatin are prone to CRF. With radiotherapy, the effects of radiation are cumulative, and patients will often not develop CRF until after a few weeks of treatment. Immunotherapy treatments with cytokines like interferons and interleukins can be toxic in high amounts and are associated with persistent CRF. Bone marrow transplants frequently cause extended fatigue, lasting as long as a year. Taking multiple anticancer drugs at once or having successive regimens increases the likelihood that a patient will develop CRF.

Evaluating Patients for Fatigue

No objective tests exist for determining whether a patient is suffering from CRF. Patients may complain that their limbs feel heavy, they have trouble thinking, and they lack energy for ordinary activities. Even walking from one room to another seems like a journey. Dr Anthony noted that CRF may be greater in the morning than other times.

Screening.NCCN guidelines recommend screening pediatric and adult patients for fatigue at their initial consultation, at each chemotherapy visit, and regularly during treatment and after treatment. CRF is subjective, and the NCCN advises asking patients >12 years of age, “How would you rate your fatigue on a scale of 0 to 10 over the past 7 days?,” with 0 being no fatigue and 10 the worst imaginable (alternatively, ask them to rate fatigue as none, mild, moderate, or severe). For children aged 7 to 12 years, use a 1 to 5 scale, with 5 being the worst. Children aged 5 to 6 years should be asked if they are “tired” or “not tired.”

On the severity scale, NCCN rates responses of 0 to 3 in adults, 1 to 2 in the 7- to 12-year age bracket, and “not tired” in 5- to 6-year olds as none to mild CRF. In adults, moderate CRF is defined as 4 to 6 and severe as 7 to 10; in children aged 7 to 12 years, 3 is considered moderate and 4 to 5, severe; and in children aged 5 to 6 years, a response of “tired” can indicate moderate or severe CRF.

Confirming CRF. In patients found to have CRF, ask about its progression, whether anything seems to relieve or exacerbate fatigue and the extent to which it interferes with everyday activities. There are also various questionnaires and assessment tools available to help evaluate the extent of a patient’s fatigue. Review any changes in the use of prescribed or over-the-counter medications or supplements. Beta-blockers, certain antidepressants, and antihistamines often contribute to fatigue.

Dy et al advise evaluating patients with newly identified fatigue for depression and insomnia. Fatigue is often a sign of recurrence or progression, and NCCN recommends ruling these out in patients with CRF. Other causes of fatigue include pain, anemia, poor nutritional status, and reduced activity. It is also important to look for comorbidities, such as diabetes, infection, dysfunction in various organs, or thyroid disorders.

Treating CRF

Fatigue is considered one of the most emotionally stressful adverse effects of cancer. In some patients, severe or persistent CRF diminishes their interest in efforts to get better, and they are more likely to miss therapy sessions. They may also miss work, possibly affecting their finances, which, in turn, affects their ability to afford treatment. NCCN recommends advising patients with cancer and their families that managing fatigue is an important part of any treatment plan.

Any secondary causes of fatigue should be addressed; correcting abnormal blood counts, restoring electrolyte balance, or correcting thyroid function can alleviate fatigue in some patients. Pharmacological treatments for depression and insomnia appear to have little effect on CRF, and recent studies indicate psychosocial therapy is also not curative. Typically, even after CRF is diagnosed and addressed, the patient does not get better completely.

Nonpharmacologic Management of CRF. NCCN guidelines offer several nonpharmacologic options to help manage CRF, including exercise. It was once thought that physical exertion and lack of rest contributed to fatigue, but numerous studies show patients who decrease activity and take extended naps actually suffer worse CRF. Several recent studies, including at least 3 published this year, have found that exercise improves CRF in patients with cancer.

Cramp and Daniel (Cochrane Database of Systematic Reviews,2008) conducted a meta-analysis of 28 studies (N = 2083) that included data on fatigue. In comparing the 920 participants who received exercise intervention with 742 controls who did not, they determined that “exercise was statistically more effective than the control intervention.” Dy et al conducted their own meta-analyses of at least 30 studies that examined the relationship between fatigue and exercise and concluded that the effect of exercise on CRF was not significant. NCCN guidelines support encouraging patients to engage in activity but say there is not enough evidence to recommend a specific program.

At the 2008 ASCO Annual Meeting, Ferrell et al presented data from a study that showed 101 patients with solid tumors benefited from a 4-part interventional program that included information on managing fatigue and pain compared with 83 patients in a control group who received usual standard care. The authors noted, “Fatigue decreased significantly in the intervention sample (P = .006 to P <.001) and increased in the usual care sample.”

A 2009 study by Windsor et al found that patients undergoing radiotherapy and chemotherapy who received written information on fatigue and exercise were more likely to exercise during treatment and had a “significant overall increase in mean fatigue from the start to the end of cancer treatment.” The authors said patients who did not exercise, younger patients, and patients with breast cancer had higher fatigue scores. Those receiving chemotherapy also had higher fatigue scores than similar patients receiving radiotherapy. According to NCCN, exercise may not be appropriate for patients with bone metastases, immunosuppression/neutropenia, thrombocytopenia, anemia, fever, infection, or other limiting comorbid conditions.

In addition to exercise, several studies support stress management support groups, counseling, and other psychosocial interventions to reduce CRF. Attention-restoring therapy, nutrition consultation, and sleep therapy have also been shown in some studies to have a positive effect on CRF.

Pharmacologic Management.There is little evidence supporting use of any pharmacologic products to manage fatigue, other than those used to treat cancer-related anemia. A small number of studies showed that some patients who received pharmacologic interventions for anorexia-cachexia, such as megestrol or medroxyprogesterone acetate, experienced improved CRF as an indirect benefit.

NCCN says stimulants such as methylphenidate can be considered after ruling out other causes of fatigue. The guidelines also note that while at least 2 studies have found benefit from the anti-narcoleptic agent modafinil (Provigil), there is not enough evidence to recommend it for patients with CRF. In a 2006 study by Morrow et al, published in Clinical Oncology, modafinil showed significant benefit only in patients with severe fatigue (>6 on the acuity scale).

NCCN notes that anti-insomnia drugs may have negative adverse effects contraindicating their use and there is insufficient evidence to demonstrate that they improve CRF. A Mayo Clinic study found that 1000 to 2000 mg per day of Wisconsin ginseng significantly reduced CRF, and ongoing trials are attempting to validate these results.

CRF in Cancer Survivors

Patients may suffer from CRF for months or years after treatment ends. The exact cause is unknown, but certain biomarkers have been implicated. These include higher serum markers interleukin-receptor antagonist, soluble tumor necrosis factor type II, and diminished cortisol levels. Survivors with persistent CRF after treatment were found to have significantly more circulating T lymphocytes, signs of a chronic inflammatory process.

Anemia in Patients with Cancer

Nearly one-third of patients with cancer develop anemia, indicated by a lack of or misshapen red blood cells. It is a common cause of CRF. Anemia is a multifactorial condition, having many possible causes. In some patients, the neoplasm is responsible; in others, treatment may be causative or it may result from an underlying comorbid condition. Estimates suggest 40% to 60% of patients have anemia at diagnosis, although it is more prevalent with some cancers than others. For example, 32% of patients with non-Hodgkin lymphoma have anemia at diagnosis, as well as 49% of patients with gynecological cancer and 80% of patients with multiple myeloma. Anemia is also more common in patients with uterine-cervical cancers and cancers that cause renal impairment. There are various independent predictors for anemia risk.

According to the NCI, anemia is defined as a hemoglobin (Hb) level of 14 g/dL to 18 g/dL in men and 12 g/dL to 16 g/dL in women. NCCN guidelines outline 3 acuity levels for anemia: mild, 10 g/dL to 11 g/dL; moderate, 8 g/dL to 10 g/dL; and severe, <8 g/dL. Patients who have Hb levels <12 g/dL are more likely to have fatigue, worse quality of life, diminished mental and physical performance, and poorer surgical outcomes.

Causes of Anemia

Cancer causes anemia in a variety of ways, which vary according to the type of malignancy. Certain malignancies, like those of the gastrointestinal (GI) tract, cervix, and vagina, are associated with anemia induced by exogenous blood loss. Some cases of cancer-induced anemia result from intratumoral bleeding, erythrophagocytosis, or bone marrow replacement.

Cancerous tumors also produce amyloids, antibodies, and procoagulant proteins that can lead to anemia. Cytokines produced in cancer patients, including tumor necrosis factor and interleukin-1, have been found to impair iron metabolism and suppress production of erythropoietin (EPO). This hormone is produced in the kidney and stimulates the production of red blood cells in bone marrow. The exact mechanism by which cytokines inhibit EPO production is not clear.

Chemotherapy-induced anemia is a common complication of treatment using cytotoxic agents. Chemotherapy destroys red blood cells, although neutropenia and thrombocytopenia are frequently evident before a decline in red blood cells. The nephrotoxic effects of certain chemotherapy drugs—particularly, platinum-based agents&mdash;can also lead to anemia. Patients with lung cancer or gynecologic cancer have higher rates of chemotherapy-induced anemia. Platinum-based regimens are frequently used to treat these malignancies, as well as head and neck cancers.

Some newer agents are also associated with a greater risk of anemia. The majority of patients with GI stromal tumors treated with imatinib (Gleevec) develop anemia, with 10% of patients developing grade 3-4 anemia. Sunitib (Sutent) is associated with a 26% rate of anemia in patients with renal cell carcinoma. The safety of using erythropoiesis-stimulating agents (ESAs) has not been evaluated extensively with these newer anticancer agents.

Chemotherapy and cancer can compromise nutritional intake and absorption, further putting patients at risk for anemia. NCCN notes that a patient may have more than one underlying cause for anemia.

Treating Patients with Anemia

It is difficult to determine when anemia requires immediate correction. NCCN guidelines on cancer-induced and chemotherapy-induced anemia recommend complete symptom assessment for patients treated with myelosuppressive chemotherapy prior to treating. This includes evaluating objective physical symptoms that frequently develop in patients with anemia. Some patients tolerate symptoms of anemia better than others do, however, which suggests the need for laboratory tests to support a suspected diagnosis.

Transfusion. A transfusion with packed red blood cells (PRBC) is one option for correcting anemia. For patients undergoing chemotherapy with curative intent and for those who need immediate correction, transfusion is the only option. It is also an option for patients undergoing chemotherapy without curative intent. PRBC transfusion rapidly increases Hb and hematocrit levels; in the average-sized adult, 1 unit of PRBC increases Hb an average of 1 g/dL within an hour. Studies differ on whether transfusing critically ill patients improves overall survival.

The risks of transfusion include transfusion-related reactions, such as lung injury or graft versus host disease; congestive heart failure; bacterial contamination; and viral infections. The risks for bacterial and viral infection have declined since 1984, with the implementation of new methods for treating and storing PRBC. Although iron overload is possible in patients who receive multiple transfusions, this is unlikely if transfusions occur only while the patient is receiving myelosuppressive chemotherapy.

Erythropoiesis-stimulating Agents.The use of ESAs to treat anemia in patients with cancer has been the subject of a great deal of controversy. ESAs work by stimulating the bone marrow to produce new red blood cells. Years of studies have established an association between ESAs and increased mortality risk and tumor growth.

The FDA has revised the label for these drugs several times, adding black box warnings to their labels cautioning oncologists on their use in patients with cancer. An FDA safety committee continues to evaluate the ESAs epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). There is speculation that ESA use may eventually be prohibited in this patient population. NCCN notes that the current blood supply in the United States is insufficient to treat all patients with cancer who currently receive ESAs for chemotherapy-induced anemia.

Per the FDA and NCCN guidelines, ESAs should not be administered to patients receiving treatment with curative intent. For those whose treatment is not considered curative, NCCN advises individualized counseling that includes discussion on the risks and benefits of ESA use. Patients must also be given an FDA-approved medication guide on ESAs.

The FDA says to use the lowest effective dose of ESAs. It takes 2 weeks of ESA use to increase red blood cells. The patient’s Hb levels should be measured weekly until they stabilize. If using epoetin, ASCO recommends a 25% dose reduction when Hb approaches 12 g/dL or rises ≥1 g/dL in a 2-week period. For darbepoetin, ASCO says a 40% dose reduction is warranted when Hb rises ≥11 g/dL or increases ≥1 g/dL in a 2-week period. For those with no response after 4 weeks of epoetin alfa or 6 weeks of darbepoetin alfa, a dose increase may be needed. Parenteral iron can also increase the effectiveness of ESAs.

ESAs are associated with improvements in the quality of life for patients with chemotherapy-related anemia, particularly through a reduction in fatigue. However, they have also been found to shorten survival, accelerate tumor growth, and increase the risk for thromboembolic events, particularly in patients with Hb levels >12 g/dL. Bohlius et al (Lancet, 2009) reviewed 53 trials (N = 13,933) and found that mortality increased 17% overall in patients who received ESAs and 10% in the subset of patients on chemotherapy. A meta-analysis of 42 clinical trials (N = 12,000) by Reiman et al (Canadian Medical Association Journal, 2009) found that ESAs improved the quality of life and reduced the need for transfusions, but were also associated with a 15% increased risk of serious advents and a 16% increased risk of death. Several groups are suggesting that ESAs be restricted to those patients for whom transfusion is not an option.

At present, it is up to the patient with incurable cancer to weigh the risk of shortened life against the benefit of improved quality of life and reduced fatigue associated with the use of ESAs. Many physicians are concerned about the possibility that this treatment may be removed from their limited arsenal of options for treating anemia in patients with cancer.

Conclusions

The NCI says CRF is likely underdiagnosed. Some patients may be reluctant to report it to their physician or oncology nurse, believing it is a “normal” part of cancer. Healthcare providers need to take an active role in screening patients regularly for CRF, even after treatment is complete.

Although there are few treatments for CRF that has no underlying cause, anemia is a frequent cause of CRF and can be treated. Untreated anemia is dangerous for patients with cancer; it is an independent risk factor for mortality. CRF and anemia both erode the patient’s quality of life, making it more difficult to win the fight against cancer.