Annals of Oncology Advance Access originally published online on September 15, 2006
Annals of Oncology 2006 17(11):1705-1708; doi:10.1093/annonc/mdl297
© 2006 European Society for Medical Oncology
quality of life and supportive care |
An induction dose of epoetin 
of 40 000 IU daily for three consecutive days increases and maintains hemoglobin levels in anemic cancer patients undergoing chemotherapy
Universita' di Trieste, Centro Oncologico ASS1 triestina, Italy
* Correspondence to: Prof G. Mustacchi, Centro Oncologico, Via Pietà 19, 34100 Trieste, Italy. Tel: +39 040 3992232; Fax: +39 040 7606111; E-mail: g.mustacchi{at}fmc.units.it
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Abstract |
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Background: This pilot study was conducted to evaluate the feasibility, activity, and safety of an induction dose of epoetin
in cancer patients with moderate or severe anemia who were receiving chemotherapy.
Patients and methods: Thirty patients with solid tumors and hemoglobin (Hb) levels <11.0 g/dl were enrolled. Patients received single s.c. injections of epoetin , 40 000 IU for three consecutive days, and were then observed for the following 30 days. The primary efficacy variable was the response rate (Hb increase 
1 g/dl) at day 15. Secondary efficacy variables included the proportion of patients given blood transfusions between baseline and the end of study, the duration of response (Hb level 1 g/dl), and ability to maintain the planned chemotherapy dose (dose intensity).
Results: At day 15, 23 of 30 (77%) patients had achieved increases in Hb levels of at least 1 g/dl. The mean Hb increase in responders was 2.0 g/dl [95% confidence interval (CI) = 1.7–2.3 g/dl]. The Hb increase was 2.3 ± 0.7 g/dl in responders with baseline Hb levels <9.5 g/dl (median Hb value), and 1.7 ± 0.6 g/dl in those with higher Hb levels (P = 0.012). The median duration of response was 6.1 weeks (95% CI = 1.6–10.6 weeks). Hematologic parameters were not significantly changed in nonresponders. Multivariate analysis detected no significant differences in Hb increase at day 15 on the basis of age, sex, weight, baseline Hb levels, type or stage of tumor, or treatment with platinum-based chemotherapy. No serious adverse event related to epoetin treatment was observed.
Conclusions: We conclude that a higher initial dosing of epoetin appears to be an efficient schedule for treating anemia in cancer patients undergoing chemotherapy, conferring higher response rates than those seen with standard doses. Further evaluation of these and other epoetin dosage regimens is warranted.
Key words: anemia, chemotherapy, epoietin
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introduction |
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Large, prospective, community-based trials and randomized, double-blind, placebo-controlled trials have established the efficacy of epoetin
, administered at doses of 150–300 U/kg s.c. thrice weekly (TIW) [1, 2], 10 000–20 000 U s.c. TIW [3], or 40 000–60 000 U s.c. once weekly (qw) [4], in significantly decreasing transfusion requirements, increasing hemoglobin (Hb) levels, and improving quality of life in anemic cancer patients receiving chemotherapy. The mean increase in Hb concentrations was 
1 g/dl after 4 weeks and 2 g/dl after 8 weeks of epoetin therapy. Mean response rates in these studies ranged from 53% to 70%, response being defined as an Hb increase 2 g/dl after 12 weeks of treatment. Dosing regimens of erythropoietic agents that use higher starting doses are presently being explored for the treatment of cancer-related anemia. Such regimens have the potential to provide additional benefits to patients and health care providers beyond those currently demonstrated with standard step-up dosing. Hypothesized advantages include a more timely response to therapy, a greater proportion of patients responding, an opportunity to identify nonresponders earlier in the course of treatment, and a possible cost savings (or an improved cost–benefit ratio).
In an effort to explore the potential for even better response rates with respect to rapidity and duration of response in anemic cancer patients, a new epoetin schedule using a 3-day induction dose was evaluated. This report describes the results of a pilot study we conducted to examine the efficacy and safety of this dosing regimen in a subset of cancer patients with moderate-to-severe anemia who were receiving chemotherapy.
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materials and methods |
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patients and study design
This was a single-center, prospective, open-label, nonrandomized study. Patients enrolled in the study were required to be at least 18 years of age, a confirmed diagnosis of solid malignancy for which they were receiving platinum or nonplatinum chemotherapy, and a mild-to-moderate anemia (Hb levels <11 g/dl). In addition, they were scheduled to receive at least two other cycles of chemotherapy, and had a life expectancy of
6 months. Exclusion criteria included uncontrolled hypertension, an Eastern Cooperative Oncology Group performance status (PS) score 3, iron, folate, or vitamin B12 deficiency, prior ablative chemotherapy, a history of acute major infection within 1 month, allogeneic blood transfusion within 14 days, severe illness or surgery within 7 days of study entry, and prior treatment with erythropoietic agents. All patients provided written informed consent to participate in the study.
We hypothesized that the response rate with this new epoetin regimen should not be inferior to 70%, the best response rate obtained with conventional epoetin schedules. If a response rate 70% was observed after the first 10 patients, an additional 20 patients were to be recruited for this phase II trial.
treatment
Patients received single s.c. injections of 40 000 IU epoetin (Eprex®; Ortho Biotech, a division of JANSSEN-CILAG SpA, Cologno Monzese Milan, Italy) on study days 1, 2, and 3 (a total of three injections) and their parameters monitored every 15 days for at least 30 days. If transferrin saturation fell to 
20% during the treatment period, an oral daily dose of 200 mg elementary iron was administered.
efficacy and safety evaluations
The primary efficacy variable was the response rate at day 15. Response was defined as an increase in Hb level 1 g/dl in the absence of transfusions. Secondary efficacy variables included the proportion of patients given blood transfusions between baseline and the end of study, the duration of response (Hb level 1 g/dl), and ability to maintain the planned chemotherapy dose (dose intensity). Safety was evaluated mainly by monitoring adverse events.
statistical analysis
Continuous variables (including Hb level, change in Hb level, proportion of patients transfused, and units transfused per patient) were summarized by descriptive statistics. Categorical variables were summarized by frequency statistics. Means and standard deviations (SDs) of continuous variables and frequencies and proportions of discrete variables are reported. Changes in Hb level from baseline to day 15 were compared using Student's t-test for paired data. The chi-square test was used to compare proportions. Correlations of variables with other variables were calculated by Pearson r correlation coefficient. Multivariate analysis was carried out by least-squares multiple linear regression. P <0.05 was designated as statistically significant; all P values are two-tailed.
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results |
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The first 10 patients were recruited between September 2002 and February 2003. A response was observed in eight of these patients (80%), with no relevant toxic effects attributable to epoetin
. Following the study design, we resumed the recruitment of the additional 20 patients between April 2003 and May 2004. All patients were assessable for efficacy and safety results. Patients' demographic and clinical characteristics are summarized in Table 1. Most of the patients were women (90%), breast cancer being the most frequent primary tumor (11 of 33, 37%).
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No patient received radiation therapy while on study. All 30 patients enrolled had received prior treatment with chemotherapy within 3 months of study initiation. Chemotherapy was in the adjuvant setting for 11 of 30 (37%) patients, and in the metastatic setting for the remaining 19 patients (first line, 43%; second line, 13%; third line, 7%). The most common classes of chemotherapeutic agents were taxanes, anthracyclines, and platinum derivatives (Table 1). Anemia developed on average after the third cycle of chemotherapy (range, 1–9 cycles).
hematopoietic response
At day 15, 23 of 30 (77%) patients had achieved increases in Hb levels of at least 1 g/dl. In responders, Hb levels were 9.5 ± 0.8 g/dl at baseline and 11.5 ± 0.8 g/dl at day 15 (P < 0.001), with a mean Hb increase of 2.0 g/dl (95% CI 1.7–2.3 g/dl). Hb levels remained <11 g/dl in seven (30%) responders, reached concentrations in the 11–12 g/dl range in 10 (44%), and exceed 12 g/dl in six (26%). The highest Hb value recorded was 13.2 g/dl. There was an inverse correlation between baseline Hb levels and Hb increase (r = –0.4569; P = 0.028; Figure 1). The Hb increase was 2.3 ± 0.7 g/dl in responders with baseline Hb levels <9.5 g/dl (median Hb value), and 1.7 ± 0.6 g/dl in those with higher Hb levels (P = 0.012). The median duration of response was 6.1 weeks (95% CI 1.6–10.6 weeks).
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Hematologic parameters were not significantly changed in nonresponders. In these patients, Hb levels were 9.3 ± 0.2 g/dl at baseline and 9.3 ± 0.6 g/dl at day 15 (P = 0.2).
Multivariate analysis detected no significant differences in Hb increase at day 15 on the basis of age, sex, weight, baseline Hb levels, type or stage of tumor, or treatment with platinum-based chemotherapy.
The analysis of the effect of body weight revealed that nonresponders received a nonsignificant higher epoetin dose relative to responders (2160 IU/kg versus 1890 IU/kg; P = 0.072).
During the time of the study, transfusions were not required in responders, whereas they were given to three of seven (43%) nonresponders.
dose intensity
The dose intensity of chemotherapy tended to be maintained more easily in responders than in nonresponders. In 23 responders, there were 8 weeks of delay out of 69 cycles of chemotherapy administered, whereas in seven nonresponders, there were 6 weeks of delay out of 17 cycles of chemotherapy administered (P = 0.056).
safety
Epoetin treatment was well tolerated. No serious adverse event was considered by the investigators to be related to the study drug. One patient reported mild arthralgia/myalgia that was possibly related to epoetin administration.
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discussion |
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In this study, we evaluated the activity and safety of a new epoetin
schedule in cancer patients with moderate or severe anemia. Increases in Hb levels of at least 1 g/dl were observed in 77% of patients after 2 weeks from the start of treatment. Patients with more severe degrees of anemia (Hb <9.5 g/dl) experienced the greatest benefits in terms of Hb increase. Furthermore, most responses had a duration in excess of 6 weeks despite continued chemotherapy. Approximately one-third of our patients had a breast cancer (11 of 33) and nine of 11 were treated in adjuvant setting. Thus, it could be postulated that this predominantely healthy population is not representative of the general population. Actually the hematopoietic response in these patients was 90%. We do not think this could represent a bias because in the overall, metastatic population responders were 73.6%. Since the entry criterion was Hb level and not PS, we could argue that the ‘loading dose’ is effective and patients in good performance has more chance of response as compared to patients with a poor PS (or reduced myelopoiesis due to previous treatments).
The dosing regimen that we investigated, 40 000 IU/day for three consecutive days, was selected on the basis of available physiologic, pharmacokinetic, and pharmacodynamic data.
A pharmacokinetic and pharmacodynamic study on healthy volunteers indicates a linear relationship between response, measured as a percentage of reticulocytes area under the time-concentration curve (AUC), and erythropoietin AUC for single doses of epoetin up to 1800 IU/kg (120 000 IU). Beyond these doses, there was a saturation of response [5, 6].
On the other hand, physiology studies at high altitude and in closed-environment hypoxic atmospheres suggest that a high dose of erythropoietin is necessary for the recruitment of early precursor cells, whereas a low dose is to stimulate further differentiation [7, 8].
Results from recent clinical studies support the proposition that a high initial dose might allow for a more rapid increase of Hb levels in anemic cancer patients. In a phase II trial by Cortesi et al. [9], 19 patients with solid tumors and an initial Hb level <9 g/dl received a total of five injections of 40 000 IU epoetin on days 1, 4, 7, 10, and 13 of chemotherapy and were then observed for the following month (group A). They were compared with a historical group of 19 patients, who received 10 000 IU epoetin TIW without dose escalation for their entire treatment time of 45 days (group B). While the mean increase in Hb at day 15 was 1.7 g/dl for group A versus 0.4 g/dl for group B (P = 0.0042), average differences in Hb values of 2.9 versus 0.8 were observed at day 45. Response rates (Hb 2) at day 15 and day 45 were 37% and 84% in group A versus 16% and 21% in the control group, resulting in a lower transfusion rate and a better performance score for patients in the front-loading group. Similar results were obtained when treating lung cancer patients with the same epoetin schedule, being the mean Hb increase 2.0 g/dl at day 15 and 2.9 g/dl at day 30 [10].
Another pilot study by Patton et al. [11] in cancer patients (n = 20; Hb 11 g/dl) receiving chemo- or radiotherapy combined a loading dose of 60 000 IU epoetin /week given for 8 weeks with a maintenance dose of 120 000 IU administered every 3 weeks. The maintenance dose was only applied in case the Hb increase after 8 weeks of therapy was 2 g/dl. Total treatment time was 24 weeks. The median increase in Hb was 1.1 g/dl (week 4), 2.8 g/dl (week 8), and 3 g/dl at final measurement. While in seven patients the epoetin dose had to be reduced to 40 000 IU/week, 13 patients were enrolled in the maintenance phase. Starting with an average Hb of 13.1 g/dl at week 9, these patients had an average Hb of 13.3 g/dl after 24 weeks while on chemotherapy.
Justice et al. [12] showed that darbepoetin given at ‘dose-dense’ schedule of 4.5 µg/kg weekly (=60 000 IU/week) was able to increase the mean Hb level by 1.3 g/dl in 6 weeks. The Hb level reached was maintained throughout the 18 weeks of study in 80% of patients receiving the same dose every 3 weeks. The bias of this study is that only 52% out of 120 patients completed the study drug for several reasons.
In our study, the interesting finding is the short time to response achieved as early as 2 weeks and with a lower drug consumption.
In accordance with these studies, our findings suggest that an induction dose of epoetin may overcome a possible intrinsic resistance of hematopoietic progenitor cells and stimulate differentiation by increasing receptor saturation at an early stage. Such an event may mimic what happens naturally, and may afford a high rate of rapid response in anemic cancer patients, including those with severe anemia and a resultant highly compromised bone marrow.
In conclusion, our pilot study indicates that a higher initial dosing of epoetin appears to be an efficient schedule for treating anemia in cancer patients undergoing chemotherapy, and may confer even higher response rates than those seen with standard doses, at least in some subsets of patients. Further evaluation of these and other epoetin dosage regimens is warranted in randomized, prospectively controlled trials.
Received for publication May 23, 2006. Revision received July 6, 2006. Accepted for publication July 7, 2006.
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References |
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12. Justice G, Kessler JF, Jadeja J, et al. (2005) A randomized, multicenter study of subcutaneous and intravenous darbepoetin alfa for the treatment of chemotherapy-induced anemia. Ann Oncol 16:1192–1198.
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