Introduction

Advances in our understanding of the impact of anemia on quality of life, tolerance of therapy and response to therapy in cancer patients is progressing rapidly. The use of the two commercially available erythropoietic stimulating proteins, epoetin alfa and darbepoetin alfa, has stimulated investigations into the use of these agents in a variety of settings in cancer patients. Mature results from studies evaluating the treatment of chemotherapy-induced anemia (CIA) were a topic of much interest at 2005 meeting of the American Society of Clinical Oncology in Orlando, Fla.

Head-to-Head Comparisons

Comparative efficacy of commercially available erythropoietic stimulating proteins was explored by two randomized trials comparing darbepoetin alfa, 200 mcg every two weeks, to epoetin alfa, 40,000 units weekly, in CIA. The larger trial, a phase III open label randomized trial reported by Glaspy et al. included patients with >8 weeks of planned chemotherapy and hemoglobin levels < 11g/dl.[1]Overall, 1220 patients were randomized and 1209 receiving at least one dose of study drug were included in the primary analysis group. The primary endpoint of the trial, transfusions from week five through end of study, showed no significant difference in outcome. Twenty-one percent of patients receiving darbepoetin alfa and 16% of patients receiving epoetin alfa required a transfusion during this period. Noninferiority of one approach to the other was thus confirmed, both from the five-week point through the end of treatment and for transfusions from week one through the end of treatment. The mean improvement in hemoglobin levels showed similar results for both groups: At study week nine there was a 1.2 g/dl increase for darbepoetin alfa and 1.5 g/dl rise for epoetin alfa, and at week 17 a 1.5 g/dl rise for darbepoetin alfa and 1.6 g/dl rise for epoetin alfa (p=NS).

Patient self-reported outcomes demonstrated improvements in the FACT-F scale over time which were similar between the groups with a 4.2 point rise in patients treated with darbepoetin alfa and a 3.5 point rise for epoetin alfa treated patients. No significant differences in other QOL measures between the two groups were noted. The mean duration of dosing was similar for both drugs with 12.1 and 12.7 weeks, respectively, while patients with darbepoetin alfa received on average 6.5 doses and patients with epoetin alfa received 11.5 doses.

A smaller randomized trial of the same starting doses of epoetin alfa and darbepoetin alfa in a similar patient population was reported by Waltzman et al.[2]The primary endpoint of this trial showed superiority at week five in the proportion of patients achieving a 1 g/dl rise in hemoglobin, 47% for epoetin alfa vs. 31.5 % for darbepoetin alfa (p=0.007). However, there was no significant difference in the proportion of patients requiring PRBC transfusion from week five to end of study: 12.9% for epoetin alfa patients and 17.5% for darbepoetin alfa (p=0.29). At week nine, 65.1% of patients receiving epoetin alfa had a >1 g/dl response compared to 56.5% for darbepoetin alfa (p= 0.121). The mean rise in hemoglobin levels at end of study was 1.2 g/dl for epoetin alfa vs. 0.8 g/dl for darbepoetin alfa. Of note, prespecified escalation in the erythropoietic agent was not the same for both drugs, occurring on week five for epoetin alfa and week seven for darbepoetin alfa. The more modest overall hemoglobin responses in this study may reflectin part dosing adjustments since the mean epoetin alfa dose was 38,197 U in Waltzman’s trial compared to 42,714 U in Glaspy’s study and 209 mcg vs. 229 mcg for darbepoetin alfa, respectively.

Taken together, and consistent with a previous trial comparing the identical starting doses of epoetin alfa to darbepoetin alfa, it appears that every-two-week dosing of darbepoetin alfa yields similar erythropoetic effects to weekly epoetin alfa.[3]Patient convenience and timing of supportive care measures to match chemotherapy administration schedules may thus become important determinants of preference.

Extended Dosing Schedules for Erythropoietic Agents

Many chemotherapy regimens are given on a three-week cycle, so exploring the ability to give erythropoietin synchronized with this schedule is a valuable endeavor. Boccia et al. evaluated the effectiveness of darbepoetin alfa administered at 300 mcg q 3wk to achieve hemoglobin levels between 11 and 13 as per commonly used guidelines.[4]This single arm open label trial included anemic patients with nonmyeloid malignancies and at least eight additional weeks of planned chemotherapy. While 1500 patients will ultimately be enrolled, this interim analysis included 1225 patients. About one-third of patients had hemoglobin <10 g/dl and two-thirds had hemoglobin >10 g/dl at start. For all patients, the mean initial hemoglobin level was 10.1 g/dl. Overall, 91% of patients by the Kaplan-Meier method achieved target hemoglobin and the mean hemoglobin after achieving target was 11.5 g/dl. After achieving the target, approximately three-quarters of patients maintained their levels in their target range. Patients starting with a hemoglobin above 10 g/dl were both more likely to achieve the target level and achieved it much more rapidly than patients starting with a hemoglobin <10 g/dl. These results add to the accumulating evidence for darbepoetin alfa’s effectiveness at treating chemotherapy-induced anemia with flexibility timed to usual chemotherapy schedules.

Every-three-week epoetin alfa was evaluated in a multicenter, randomized phase III trial conducted by the North Central Cancer Treatment Group.[5]Anemic cancer patients, defined as <12 g/dl for men and <11 g/dl for women (N=365), first received three weeks of 40,000 U of epoetin alfa weekly, followed by either continued 40,000 U weekly or a switch to 120,000 U every three weeks. All patients received oral iron supplementation. The primary endpoint, PRBC transfusion requirement, was similar in both arms, 15% for 120,000 U every three week epoetin alfa vs. 23% for 40,000 U epoetin alfa weekly. However, the hemoglobin level increase was higher at end of study for the weekly treatment schedule, 12.0 g/dl vs. 11.5 g/dl (p=0.0006) and mean hemoglobin increase from baseline was also statistically better for 40,000 U weekly: 1.8 g/dl vs. 1.4 g/dl (p=0.01). It should be recognized that hemoglobin levels were determined more frequently in the 40,000 U group, and, therefore, ascertainment bias may influence these results. No significant difference in global QOL self-assessment score, FACT-AN, or other QOL score was noted. There was no difference in toxicity, with rare ischemic and thromboticevents in both arms. Therefore, for mildly anemic patients, less frequent dosing of epoetin alfa after weekly induction treatment may be an acceptable strategy.

Use of Erythropoietin in Dose Dense Regimens

Dose dense chemotherapy, commonly used now in the adjuvant treatment of breast cancer, is associated with an increased risk for anemia and a greater need for transfusions. Citron et al. presented a detailed analysis of anemia endpoints from Intergroup Trial C-9741, a four-arm trial comparing sequential adriamycin/cytoxan/paclitaxel to AC followed by paclitaxel and dose dense q 14 day chemotherapy vs. standard q 21 day schedules.[6]The dose dense arms were more effective in preventing disease recurrence and improving survival. Dose dense AC followed by paclitaxel was associated with a 13% risk of transfusion compared to 4% in the non-dose dense arm. The hemoglobin levels of each arm were presented and demonstrated an approximately 2 g/dl drop in mean hemoglobin at the end of dose dense AC followed by a gradual increase until the end of treatment. Erythropoietic agents were allowed but not specified by the protocol. In the AC followed by paclitaxel arm, >50% of patients required either a transfusion and/or an erythropoietic agent. The authors concluded that erythroid growth factors should be considered to reduce the severity of anemia in breast cancer patients receiving dose dense AC followed by paclitaxel.

Given this relatively profound anemia stimulus, the German AGO Group designed a dose dense trial which incorporated a preventive strategy with erythropoietin. This trial compared standard epirubicin/cyclophosphamide followed by paclitaxel to dose dense sequential epirubicin, paclitaxel and cytoxan (ETC).[7]Patients receiving ETC were further randomized to receive epoetin alfa 150 IU/kg TIW prophylactically at the initiation of chemotherapy vs. no erythropoietic agent. They were also interested in evaluating survival given contradictory information regarding the influence of epoetin on surviving breast cancer.

As anticipated, dose dense ETC without epoetin alfa was associated with a median 2.1 g/dl drop in hemoglobin by end of study, while median hemoglobin remained stable at 12.4 g/dl at beginning and end of study for patients receiving prophylactic epoetin alfa . The transfusion rate was 28% for dose dense ETC compared to 12% for ETC plus epoetin alfa (p < 0.0001). There was no influence of epoetin alfa on EFS or OS (p=0.91) and no difference in time to relapse (p= 0.84). This trial, therefore, lends support to the notion that erythropoetin therapy does not impact negatively on overall outcome as long as strict attention is paid to dose reductions or holding of the erythropoetic agent if the hemoglobin level rises above normal range. Moreover, early initiation of an erythropoietic agent is extremely effective.

Mild Anemia and Cancer

Guidelines for the treatment of anemia of cancer currently support initiating therapy when hemoglobin is <10 g/dl or <11 g/dl with symptoms. Little is known regarding quality of life deficits associated with mild anemia and cancer. Schwartzberg et al. retrospectively analyzed patients in a large community oncology database with mild anemia and no recent chemotherapy or erythropoetic agent.[8]The Cancer Care Monitor, a validated computerized review of symptoms QOL tool completed at each visit before knowledge of the hemoglobin level, was available for every patient. Mild anemia was defined as 12 g/dl to <14 g/dl for men and 10g/dl to <12 g/dl for women. Both mild anemia groups had more physical symptoms and impaired performance compared to age matched controls without anemia. Interestingly, men with hemoglobin 12-14 g/dl had similar self-reported symptoms of fatigue and global QOL impairment to women with hemoglobin 10-12 g/dl. These results suggest that mild anemia is associated with significant QOL decrements, which potentially could be relieved by treating anemia. Moreover, gender specific differences in hemoglobin levels suggest attention should be paid in forthcoming research trials to mild anemia, particularly in men. A hemoglobin level of 11 g/dl represents a 3 g/dl drop from normal in a man and appears to be clinically significant with regard to QOL.

Conclusion

The benefit of erythropoietic therapy in patients with cancer is well established, with the field now moving towards earlier intervention in patients with mild anemia and those with a high likelihood of developing CIA, such as patients receiving dose dense chemotherapy. Flexibility of dosing to match chemotherapy schedules by altering schedules and doses of erythropoietic agents is currently under intense evaluation. Oncologists recognize the value of maintaining cancer patients in a relatively normal hemoglobin range, and results of trials presented at the 2005 American Society of Clinical Oncology meeting aid them in routine daily clinical practice.

Disclosures

References