The role of erythropoietic management in the treatment of the cancer patient continues to evolve and expand rapidly. Several abstracts presented at ASCO in May 2003 provide insight into the role of Aranesp® (darbepoetin alfa) in this increasingly important area.

Current Standard of Treatment

The standard treatment for anemic patients receiving chemotherapy was previously recombinant human erythropoietin (rhEPO) at a dose of 40,000 U per week or 10,000 U three times weekly. If a sufficient increase in hemoglobin level is not observed after 4 weeks, the dose is increased. The literature demonstrates that this approach is associated with decreased transfusion risk and improved quality of life. ^1-4

In the only randomized clinical trial published to date in which various doses of Aranesp® were compared for their erythropoietic effects to the current standard rhEPO therapy, the lowest dose of Aranesp® which produced results indistinguishable from rhEPO was 3 mcg/kg administered every two weeks. ^4,5 Subsequent analyses have indicated that this observation is correct. ⁶

Analyses that compared the Aranesp® data from the one randomized trial to date for rhEPO from previously published studies concluded that the results with 3 mcg/kg (approximately 200 mcg total dose) every other week are inferior to the current standard. The randomized trial was carried out with an intent-to-treat approach to missing data points and with careful correction of the data to eliminate the effects of transfusions. Previously published studies utilized a less conservative available data approach to the missing data and transfusion problem. Although it is a questionable practice to accept one arm and ignore a control group from a randomized trial and replace it with historical data which was analyzed differently, these analyses have raised an important question: Does 200 mcg of Aranesp® every other week produce results indistinguishable from those observed with 40,000 units of rhEPO given weekly?

Data indicating that 200 mcg every other week is indeed equivalent continues to accumulate. Two abstracts presented at ASCO 2003 are among those. Mirtsching et al presented an analysis of pooled data from several studies in which anemic chemotherapy patients received Aranesp® 3 mcg/kg every two weeks (n=287) or epoetin alfa according to current standard (n=115). ⁷ Both groups had dose increases permitted for non-responding patients. Importantly, all of the data for all of the studies were analyzed identically, and with careful attention to eliminating selection bias associated with non-random dropouts and the effects of transfused red cells on hemoglobin levels. The results are startlingly similar for response rates, hemoglobin changes or changes in transfusion requirements. Vadhan-Raj et al reported improvements in quality of life in anemic cancer chemotherapy patients receiving Aranesp® 3 mcg/kg every two weeks. ⁸ The most notable changes were improvements in fatigue and energy level. These results are similar to those previously reported with standard doses of rhEPO.

Can we do better than the current standard?

The current approach to anemia with either agent has shortcomings. Unlike dialysis patients, cancer chemotherapy patients are usually treated with rhEPO or Aranesp® for 22 weeks or less. We know from studies that utilized intent-to-treat approaches to data analysis and therefore do not select for the subset of patients who have an early response that the median time to response for rhEPO given at 40,000 U per week or Aranesp® given at 200 mcg every other week is approximately 10 weeks. Moreover, many patients (approximately 40% depending upon the series) do not experience a 2 gm/dL hemoglobin increase over a 12 week study period. When the dose response curve for Aranesp® was characterized, doses were found that produced responses in most if not all patients and also decreased the time to response to approximately 7 weeks. ⁹ There was an apparent plateau on the dose response curve and higher Aranesp® doses were not associated with further improvement in response or time to response. 

Frontloading of erythropoietic agents

It has been shown in randomized pilot trials that utilizing the plateau dose of Aranesp® (4.5 mcg/kg/week) for four weeks, followed by lower maintenance doses, produces faster responses and greater improvements in quality of life than rhEPO given in accordance with the current standard. ¹⁰ Some have termed this approach “frontloading”. The use of optimal therapy initially rather than building toward it through dose increases seems particularly adapted to the significantly anemic, symptomatic cancer chemotherapy patient in whom rapid relief is crucial. At ASCO 2003, three abstracts were reported regarding frontloading of erythropoietic agents in oncology.

We reported that, throughout the 12 weeks of observation, frontloaded Aranesp® was superior to traditional doses of epoetin alfa in terms of quality of life improvement and fatigue reduction. ¹¹ These results came out of an exploratory analysis of two studies that have used the “frontloading” dosing of Aranesp® (n=74) and compared the quality of life change scores to those observed with traditional rhEPO therapy (n=104) from the same database.

Our observations were supported by an interesting report by Jumbe et al. ¹² These investigators have utilized a very large database linking Aranesp® dosing and schedule to pharmacokinetic and pharmaodynamic data and hemoglobin changes to generate a computer model which has accurately predicted the results of clinical trials with this drug. This model was utilized to compare frontloaded Aranesp® with Aranesp® given at the dose currently employed in oncology, 200 mcg every two weeks. These researchers concluded that frontloading would yield more consistent hemoglobin increases. Frontloading of Aranesp® has been studied in a large randomized trial that is now complete. The results should be available by ASCO 2004.

Finally, results from a small uncontrolled trial show that some patients can be effectively treated with the maintenance schedule of 60,000 U weekly until a hemoglobin increase had occurred, then decreased to 120,000 U every three weeks. However, it is difficult to compare these data to the frontloaded Aranesp® data for two reasons. First, there has not been a study documenting that 60,000 U per week is the optimal starting dose for rhEPO. Higher doses may yield faster responses in more patients. Second, the study did not utilize an intent-to-treat approach (n=20 at baseline, n=13 at termination, with the primary analysis restricted to a subset of patients who remained on study).

Both the Aranesp® and rhEPO “frontloading” data suggest that it is better to treat patients before they are severely anemic, with therapy started as soon as hemoglobin level falls below 12 g/dL. This approach is superior because: 1) lower less frequent dosing of drug is required to maintain than to treat and the therapy is therefore more cost effective, and 2) patients do not have to suffer compromised functional status and worsened fatigue while they wait to respond to therapy. Thus, “prevention” should increasingly become the focus of future studies.

Synchronous treatment with erythropoietic agents and chemotherapy

The effect of chemotherapy on the efficacy of erythropoietic agents is another important area that was addressed at ASCO 2003. Although it is known that synchronous administration of erythropoietic agents on the same day as chemotherapy is safe, the effects of chemotherapy on the efficacy of these drugs has never been studied. This issue becomes critically important as we begin to contemplate Aranesp® dosing schedules in which all doses of drug would potentially be given on the same day as chemotherapy (every three weeks with some chemotherapy, every two weeks with dose dense adjuvant breast cancer chemotherapy). We know that chemotherapy increases endogenous erythropoietin levels and prolongs the half-life of Aranesp®. We suspect it also decreases the marrow’s response to Aranesp®. Which effect predominates? Is it better or worse to dose synchronously?

Henry et al evaluated the effects of synchronous (same day) or asynchronous (seven days removed) Aranesp® therapy in an elegant randomized study. ¹³ Aranesp® was administered at a starting dose of 6.75 mcg/kg every three weeks in patients receiving both the chemotherapy and Aranesp® on an every three week schedule. The effects on Aranesp® pharmacokinetics and on hemoglobin response were studied. Results showed that synchronous chemotherapy had a profound effect on Aranesp® by prolonging its half-life, decreased responsiveness of the marrow/erythron, and apparently decreasing red cell survival. The effects precisely cancelled each other, and the overall response in terms of hemoglobin change were the same with asynchronous and synchronous dosing. This remarkable finding is very important. These authors also reported a response rate to every three week Aranesp® used at this dose at least as good as we have observed with standard dosing and schedules of rhEPO and Aranesp®.

Conclusion

In conclusion, the following messages emerged from ASCO 2003:

• Treatment with Aranesp® at a dose of 200 mcg every two weeks produces responses indistinguishable from standard rhEPO dosing in terms of hemoglobin, transfusion reduction, and quality of life improvement.
• For symptomatic patients with anemia, frontloading with will probably prove superior.
• It is probably better to treat patients with anemia before symptoms occur and anemia is severe.
• Synchronous dosing of Aranesp® and chemotherapy is effective; dosing with 6.75 mcg/kg every three weeks provides very promising results in chemotherapy patients.

References

1. Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997;15:1218-34.

2. Demetri GD, Kris M, Wade J, et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998;16:3412-25.

3. Littlewood TJ, Bajetta E, Nortier JW, et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19:2865-74.

4. Gabrilove JL, Cleeland CS, Livingston RB, et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001;19:2875-82.

5. Glaspy J, Jadeja JS, Justice G, et al. A dose-finding and safety study of novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia in patients receiving multicycle chemotherapy. Br J Cancer 84 Suppl 2001;1:17-23.

6. Glaspy JA, Tchekmedyian NS: Darbepoetin alfa administered every 2 weeks alleviates anemia in cancer patients receiving chemotherapy. Oncology (Huntingt) 2002;16:23-9.

7. Mirtsching B, Beck J, Charu V, et al. Darbepoetin alfa administered every two weeks (Q2W) reduces chemotherapy-induced anemia (CIA) to the same extent as recombinant human erythropoietin (rHuEPO) but with less-frequent dosing. Proc Amer Soc of Clin Oncol 2003. Abstract 2944.

8. Vadhan-Raj S, Schreiber F, Thomas L, et al. Every-2-week darbepoietin alfa imporves fatigue and energy ratign scores in cancer patients (pts) undergoing chemotherapy. Proc Amer Soc of Clin Oncol 2003. Abstract 2942.

9. Glaspy JA, Jadeja JS, Justice G, et al. Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. Br J Cancer 2002;87:268-76.

10. Glaspy JA, Jadeja JS, Justice G, et al. A randomized, active-control, pilot trial of front-loaded dosing regimens of darbepoetin-alfa for the treatment of patients with anemia during chemotherapy for malignant disease. Cancer 2003;97:1312-20.

11. Glaspy JA, Tchekmedyian N, Erder M, et al. Early and sustained improvement in health-related quality of life (HRQOL) was observed with frontloaded darbepoetin alfa compared to conventional therapy. Proc Amer Soc of Clin Oncol 2003. Abstract 3063.

12. Jumbe N, Heatherington A. Darbepoitin alfa rational dose/schedule evaluation based on quantitative understanding of erythropoiesis for early and sustained alleviation of anemia. Proc Amer Soc of Clin Oncol 2003. Abstract 3077.

13. Henry D, Patel R, Tchekmedyian S, et al. A phase 2 randomized study evaluating the timing of darbepoetin alfa administration relative to chemotherapy. Proc Amer Soc of Clin Oncol 2003. Abstract 3162.