Supportive Care: More Than Just Treating Cancer

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Introduction

Strides made in the treatment of metastatic breast cancer (MBC) appear to prolong survival in some settings, but the cost in terms of quality of life (QOL) remains a concern. The previous four E-Updates in this series on metastatic breast cancer have focused on the various treatment options, including chemotherapy, anti-HER2 targeted therapy, antiangiogenic therapy, and hormonal therapy. In this E-Update, we turn to the role of supportive measures in the treatment of cancer, specifically as these measures relate to quality of life. These measures include the use of erythropoiesis-stimulating agents (ESA) and bisphosphonates, management of fatigue and pain, and psychological care.

Clinical opinions expressed in this program are those of the authors and do not necessarily reflect the opinions of the supporters, publishers, editors, or officers of CMPMedica or Beam Institute.

Erythropoiesis-Stimulating Agents

Anemia is common in patients with cancer and is usually due to the disease itself or to the anticancer therapy. Anemia has a substantially negative impact on patients’ quality of life (QOL), inducing fatigue, reducing exercise tolerance, and possibly necessitating a reduction in the treatment dose or delay in the cycling of treatment.^1,2

Before recombinant human erythropoietin became available in 1993, red blood cell (RBC) transfusion was the only standard option for the treatment of most anemia. Currently, three erythropoiesis-stimulating agents (ESAs) are used for the treatment of chemotherapy-induced anemia:

• epoetin alfa (Epogen, Procrit, Eprex/Epypo);
• epoetin beta (NeoRecormon), not marketed in the United States; and
• the longer acting darbepoetin alfa (Aranesp)

The American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) first published evidence-based practice guidelines on the use of these agents in 2002³ and the update committee revised the guidelines in 2007.⁴ Based on a comprehensive review comparing outcomes of patients with chemotherapy-induced anemia taking either epoetin or darbepoetin, the update committee found that these agents are equivalent in efficacy and safety at the approved doses recommended by the US Drug and Food Administration (FDA).⁴ In addition, in 2006, the BlueCross and BlueShield Association Technology Evaluation Center, under the Agency for Healthcare Research and Quality (AHRQ), conducted a Comparative Effectiveness Review (CER) of the use of epoetin or darbepoetin for managing anemia in patients being treated for cancer.⁵ The CER found that epoetin and darbepoetin were equivalent in terms of hematologic response rates, transfusion rates, and thromboembolic risks.

When to Initiate ESA for Chemotherapy-Induced Anemia

Hemoglobin Concentration Approaching or < 10 g/dL
The ASCO/ASH 2007 guidelines recommend that epoetin (alpha or beta) or darbepoetin may be used in patients with chemotherapy-induced anemia and hemoglobin (Hgb) approaching or < 10 g/dL.⁴ RBC transfusion is also an option.

A meta-analysis by Seidenfeld et al of controlled clinical trials using epoetin found that the strongest evidence that epoetin decreases the need for RBC transfusions and improves QOL outcomes came from trials in patients with Hgb of 10 g/dL or less.⁶ This meta-analysis also found insufficient data that using epoetin therapy at Hgb > 10 g/dL resulted in fewer RBC transfusions or improved QOL than did starting at Hgb ≤ 10 g/dL.

The AHRQ CER identified three important studies that compared the effects of immediate vs delayed ESA treatment on transfusion rates, thromboembolic events, QOL, and survival. In each of these trials, patients were randomized to the “immediate” or “delayed” arm and ESA was given when Hgb fell to a prespecified level. In all three trials, transfusion rates were higher in the delayed arms, but the differences were not statistically significant.^7-9

Straus et al⁸ reported a higher thromboembolic rate in the immediate arm (11%) than in the delayed arm (3%), but no differences in clot risks were seen in the other two studies by Crawford et al⁷ or Reardon et al.⁹ Straus et al also found an improved QOL in the immediate arm as measured by the physical and functional well-being subscales of the Functional Assessment of Cancer Therapy-General (FACT-G), the anemia scale (FACT-An), and the fatigue subscale of the FACT-An.⁸ The other two studies, however, saw no differences in QOL between the immediate and delayed treatment arms.^7,9

The AHRQ CER advises that the data on QOL improvement with ESAs are inconsistent and should be interpreted with caution.⁵ QOL is more difficult to measure than Hgb levels or transfusion changes. Furthermore, many older studies did not report QOL data. To date, it is not clear if ESAs significantly improve QOL outcomes.

Hemoglobin Concentration > 10 g/dL but < 12 g/dL
The ASCO/ASH 2007 guidelines recommend that for patients with less severe anemia (> 10 g/dL but < 12 g/dL), the decision to use or not use ESA should be based on clinical circumstances.⁴ For example, ESAs may be considered in elderly patients with limited cardiopulmonary reserve, cardiac disease or symptomatic angina, limited exercise capacity or energy, or ability to carry out activities of daily living (ADL). RBC transfusion is also an option.

Starting/Escalating Doses of ESAs and Reducing/Discontinuing ESAs

The ASCO/ASH 2007 guidelines for ESA dosing and adjustments are based on the US FDA recommendations (Table 1).⁴

Click to enlarge

Starting and Escalating Doses
The starting dose for epoetin is 150 U/kg 3 times a week and the dose can be increased to 300 U/kg 3 times a week if there is no reduction in transfusion requirement or increase in Hgb after 8 weeks. Epoetin can also be given as 40,000 U weekly and can be increased to 60,000 U weekly if there is < 1 g/dL Hgb increase after 4 weeks.

For darbepoetin, the starting dose is 2.25 ug/kg weekly and the dose can be increased to 4.5 ug/kg if there is < 1 g/dL Hgb increase after 6 weeks. Darbepoetin can also be started at 500 ug every 3 weeks.

Alternative doses or schedules, although they may be more convenient, have not shown differences in outcomes for Hgb response or transfusion.

Reducing Doses
Recommendations for dose reducing ESA call for decreasing the epoetin dose by 25% when the Hgb approaches 12 g/dL or Hgb increases by > 1 g/dL in 2 weeks.

For darbepoetin, recommendations call for reducing the dose by 40% when the Hgb exceeds 11 g/dL or Hgb increases by > 1 g/dL in 2 weeks.

Withholding Doses
If the Hgb exceeds 12 g/dL, the epoetin dose is withheld until Hgb is < 11 g/dL and can be restarted at a 25% reduction from the previous dose.

Likewise, darbepoetin should be withheld if the Hgb exceeds 12 g/dL and until the Hgb is equal to 11 g/dL, but then restarted at a 40% reduction from the previous dose.

If there is no response to ESA, defined as < 1 to 2 g/dL Hgb rise and no reduction in RBC transfusion requirement, after 6 to 8 weeks of treatment, then ESA should be discontinued.

Iron Supplementation with ESAs

The ASCO/ASH 2007 guidelines⁴ do not differ from the 2002 guidelines³ for iron monitoring and supplementation during ESA treatment. Both sets of guidelines recommend periodic measurements of iron, total iron-binding capacity, transferring saturation, and ferritin levels and iron repletion when indicated. These measurements may be valuable in limiting the use of ESA and maximizing outcomes, but there is not enough evidence to specify the exact timing, frequency, or testing regimens for this monitoring.

Can Erythropoietic Agents Worsen Outcomes?

The possible benefit of erythropoietic agents has been challenged by two negative studies. In the Breast Cancer Eprex Survival Study (BEST), 939 patients with metastatic breast cancer receiving first-line chemotherapy were randomized to receive epoetin alfa or placebo.¹⁰ This study was terminated early because there was a higher mortality in the epoetin arm than in the placebo arm at 12 months. This was attributed to a higher rate of breast cancer progression (6% vs 3%) and higher incidence of fatal thrombotic and vascular events (1% vs 0.2%) in the epoetin alfa treated arm than in the placebo arm.

A study evaluating the effect of epoetin beta on the outcome of head-and-neck cancer patients treated with radiation therapy, also had a negative result.¹¹ In this European multicenter trial, 351 patients with anemia (Hgb < 12 g/dL for women and < 13 g/dL for men) undergoing radiation were randomized to placebo or epoetin beta 300 U/kg 3 times weekly from days 10 to14 prior to and continuing throughout radiation therapy. The therapeutic goal was a normalization of the Hgb to > 14 g/dL in men and > 13 g/dL in women. In this study, the locoregional progression-free survival (PFS) was worse in the epoetin beta-treated group (relative risk [RR] 1.62; P = .0008). Overall survival (OS) was also worse (RR 1.39; P = .02). The incidence of vascular disorders (venous thrombosis, pulmonary embolus, cerebrovascular events, hemorrhage, and hypertension) was higher in the epoetin beta-treated group (11% vs 5%). Interestingly, more than 30% of patients did not receive radiation per protocol. When the data were analyzed for those who did receive radiation, there was no difference in PFS or OS.

The design of these two trials was criticized because the enrolled patients were treated to a higher target Hgb level than the optimal level of 12 g/dL recommended by the National Comprehensive Cancer Network guidelines.¹²

In March 2007, Amgen reported the results of study 20010103 to the US FDA. This was a randomized phase III trial of darbepoetin vs placebo in a group of 989 patients with malignancies.⁴ The most common cancers were non–small-cell lung cancer (18%), breast cancer (13%), and prostate cancer (11%). The primary endpoint was the proportion of blood transfusions. Secondary endpoints were first occurrence of transfusion from week 5 to week 17, Hgb change, OS, and safety. There was no difference in transfusion requirement (hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.62-1.17). OS was worse in the darbepoetin-treated group (HR 1.30; 95% CI 1.07-1.57; P = .008). There was also an increased incidence of thromboembolic events in the darbepoetin-treated group (3.1% vs 1.3% for placebo). This led to a black-box warning on the prescribing information for epoetin and darbepoetin that ESAs are not indicated for cancer patients who are not receiving chemotherapy or radiotherapy.

What are the potential reasons for the negative outcomes seen with ESA? It is possible that ESAs bind to and activate Epo receptors (EpoRs) on the cell surface of tumors, causing nonerythropoietic responses, such as enhancing tumor growth. Recently, there are several reports on the presence of EpoRs on various tumor types including breast cancer, endometrial cancer, cervical cancer, melanoma, lung cancer, papillary thyroid cancer, and head and neck squamous cancers.¹⁴ While ongoing work is evaluating this theory, ESAs should be used judiciously.