Introduction

Anemia frequently results from cancer and its treatment and leads to fatigue, poor exercise tolerance and other symptoms.  With the advent of erythropoetic agents, such as epoetin alfa (Procrit®) and darbepoetin alfa (Aranesp®), it has become possible to treat anemia.  However, many questions remain regarding appropriate treatment of anemic cancer patients.  The 40th Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2004 provided some of the answers. 

Quality of Life Associated with Anemia

It is well established that improvement in hemoglobin levels as a response to erythropoietic agents is linked to self-reported, health-related outcomes such as improvement in fatigue, reduction in anemia-related symptomology, and overall improvement in global quality of life (QOL).  Several QOL tools have been developed to aid in the translation of subjective findings into a reproducible, clinically relevant scale. The MD Anderson Symptom and Inventory (MDASI) is a validated tool measuring the severity and impact of cancer-related symptoms.  Cleeland, et al.¹ used the MDASI to prospectively analyze changes in symptoms when anemia patients were treated with Aranesp® 200 mcg every two weeks.  Anemia-related items such as fatigue, disturbed sleep and lack of appetite showed proportionally greater improvements for patients achieving higher hemoglobin change scores at the end of the study.  Items that interfered with patients’ functioning also improved significantly, as did activity-related scores.  There was good correlation of MDASI scores with FACT-F scores.  The scale and its subsets may be useful in quantifying QOL changes during erythropoietic therapy.

Cella, et al.² reported the relationship between FACT-F scores, anemia treatment with Aranesp®, and self-reported physical function.  Anemic patients receiving Aranesp® 3.0 mcg/kg every 2 weeks completed the FACT-F questionnaire at regular intervals and were also queried about their physical ability to walk and climb stairs. The mean change in FACT-F scores was 4.6 points at 9 weeks and 6.8 points at 17 weeks of treatment. A three-point rise in this scale is considered clinically relevant.  There was a generally linear relationship between FACT-F scores and mean scores in physical functioning, implying that the FACT-F score can be used to predict the general functional level of patients. For example, a raw score FACT-F of 25 (the median point on the scale) typical for anemic cancer patients, indicates 25% of patients will be unable to walk a block and two-thirds will be unable to walk a mile.  Linking self-reported QOL scores to physical functioning may help physicians communicate to patients some of the benefits of reducing anemia. 

Striker, et al.³ examined the effect of adjuvant chemotherapy for breast cancer on development of anemia and impact on QOL. Over 50% of women developed grade I/II anemia by the fourth cycle of Adriamycin® and Cytoxan®, which persisted through sequential taxane therapy.  Patients with hemoglobin <11.5 g/dl had more QOL impairment as measured by linear analog scale or Piper fatigue scale, which was both clinically and statistically significant.  Fifty-nine percent of patients with hemoglobin <11.5 g/dl had moderate to severe fatigue, compared to 38% with hemoglobin >11.5 g/dl during adjuvant chemotherapy. Management of anemia during adjuvant chemotherapy may diminish fatigue and improve QOL.  To that end, Fastenau, et al.⁴ evaluated improvement in QOL after early hemoglobin rise in patients receiving Procrit®.  Patients with a 1-g/dl rise in hemoglobin after four weeks on study had significantly improved self-reported QOL, as measured by LASA scales, FACT-F and FACT-AN.

Erythropoetic Agents and Schedules

Uncertainties remain regarding the relative efficacy and optimal scheduling of the available erythropoetic agents, Procrit® and Aranesp®.  Several studies reported at ASCO this year helped clarify the situation. Rearden, et al.⁵ reported a trial of Aranesp® for chemotherapy-induced anemia randomizing patients to initiate therapy early at Hb <12 g/dl versus waiting until Hb was <10 g/dl.  Both groups received Aranesp® 300 mcg every three weeks. By week 13 of the study, moderate anemia (defined as a Hb <10 g/dl) developed in 29% of patients in the early intervention group, compared to 66% of patients in the late intervention group.  Interestingly, even in the late intervention group, once Aranesp® was initiated, the gain in hemoglobin was substantial.  By week 7, after two injections of Aranesp® on an every-three-week basis, the mean hemoglobin had risen by 1.5 g to 11 g/dl in the late intervention group. Both the early and late intervention groups maintained hemoglobin levels in the 11-13 g/dl “target zone” defined by NCCN guidelines for up to 18 weeks of treatment with every-three-week Aranesp®.  FACT-F scores were better for the early intervention group at week 12, but not statistically significantly different between groups by week 22 at the end of the study.  Importantly, fewer patients in the early intervention group required a transfusion (17% vs. 26%).  It appears most beneficial to initiate erythropoetic therapy early to achieve maximal hemoglobin change, transfusion reduction, and early as well as late QOL improvement.

The mature results of a randomized head-to-head comparison of Procrit® to Aranesp® in chemotherapy-induced anemia were also reported.⁶   Approximately 300 patients were randomized to receive Procrit® 40,000 units weekly versus Aranesp® 200 mcg every two weeks.  The mean starting hemoglobin was 10.4 g/dl in both groups and the patients were well balanced with regard to diagnosis and pretreatment characteristics. Results are summarized in Table 1.

Table 1:

No significant differences in any of the clinical endpoints were detected. Over 80% of patients in both arms achieved a target hemoglobin of >11 g/dl and the large majority had sustained improvements.  A major endpoint of the trial was validation of a patient satisfaction questionnaire.  Patients preferred less frequent clinic visits for erythropoetic therapy.  Similar results were noted by Tauer, et al.⁷ in a survey of 1,960 patients at 72 outpatient oncology clinics.  Clinic visits have a major impact on patients and caregivers in terms of missed work and leisure activities, as well as out–of-pocket expenses.

Waltzman, et al.⁸ also reported performing a randomized trial comparing Procrit® 40,000 units weekly to Aranesp® 200 mcg every 2 weeks and reported preliminary results this year.  At the end of the study, hemoglobin change scores were 1.5 and 1.4 g/dl for Procrit® and Aranesp®, respectively. Improvement in hemoglobin at earlier time points at 4, 8 and 12 weeks favored Procrit® by a 0.3 to 0.5 g/dl margin, but no statistically significant difference between the agents was reported. Final results are pending. Over the course of therapy, there appears to be little difference in efficacy between Procrit® dosed weekly and Aranesp® dosed every two weeks. 

Aranesp® also appears effective in the anemia of cancer.  A randomized controlled study compared Aranesp® 3 mcg/kg every two weeks versus observation for 12 weeks.⁹ Aranesp® treatment reduced transfusion requirements (10% vs 30%), showed greater change in Hb (2.1 g/dl vs. 0.3 g/dl), and showed improvement in FACT-F score (5.7 points vs. 2.2 points).  Stratification by baseline hemoglobin suggested that patients with anemia of cancer derive important clinical benefit regardless of baseline anemia level, but earlier intervention optimizes management. 

Treatment of mild anemia with Procrit® in patients receiving platinum-based chemotherapy was reported by Savonije, et al.¹⁰ Patients with baseline mean hemoglobin 10.7 g/dl were randomized to Procrit® 10,000 TIW or best supportive care. Hematopoietic response was 76% vs. 45% (p<0.05) and transfusion rate was 37% vs 65% (p<0.05).  QOL as measured by FACT-F improved by 4.0 points in the Procrit® group, while it declined by 3.7 points in the support group.  Early intervention in Grade I anemia substantially benefits patients receiving platinum chemotherapy.

Response to Erythropoietic Agents

Can we pick the patients more likely to respond to erythropoetic agents?  How much workup is necessary to evaluate nutritional factors before initiating erythropoetic therapy?  Two papers at ASCO addressed these issues. Henry, et al.¹¹ systemically evaluated anemic cancer patients who were presumably eligible for an Procrit® trial.  Surprisingly, 17% of patients had ferritins less than 100 mg/dl and 77% of these patients had TSAT <20%.  In addition, 5% of patients had B-12 deficiency, although only a minority of these had an elevated MCV value.  They concluded that a basic workup to rule out treatable causes of anemia should be performed before initiating erythropoietic therapy. 

A fraction of patients do not respond well to erythropoetic therapy. It would be desirable to identify them a priori.  Vadhan-Raj, et al.¹² studied baseline characteristics that correlate with the response to Aranesp® in a large open label trial.  Exploratory CART analyses used transfusion rate, change in FACT-F scores, and hemoglobin change to identify predictive baseline variables. The higher the baseline hemoglobin, the lower the risk of transfusion, but also the lower the change in hemoglobin at the end of treatment. Patients with breast cancer and genitourinary cancers had higher hemoglobin change and improvement in FACT-F scores than those with other tumors.  Non-platinum-containing therapies significantly impacted the risk of transfusion (odds ratio, 0.52) and increased hemoglobin change by mean 0.33 g/dl greater than platinum regimens.  Earlier intervention with erythropoetic agents at higher but still anemic hemoglobin levels may lower the risk of transfusions.  Prospective trials are currently being performed to confirm these exploratory findings, which will certainly help patient selection in the future.

Conclusion

All told, the science and clinical development of erythropoietic therapy continues to develop at a rapid pace. Improving quality of life for people dealing with the dual burdens of cancer and chemotherapy is a laudable goal.  Reversing anemia associated symptoms and improving anemia related fatigue is a reality using erythropoetic therapy.  Further research involving anemia’s impact on chemotherapy dose delivery, disease outcome and cognition is actively being explored.