V O L U M E
`
`2 2
`
`䡠 N U M B E R 7
`
`䡠 A P R I L
`
`1
`
`2 0 0 4
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From Averbach Hematology-Oncology,
`Baltimore, MD; New York University
`School of Medicine, New York, NY; De-
`partment of Statistics, Rutgers Univer-
`sity, New Brunswick; Watson Laborato-
`ries, Morristown, NJ; Mount Sinai
`Medical Center, Miami Beach, FL;
`Mount Ayr Medical Center, Mount Ayr,
`IA.
`
`Submitted August 18, 2003; accepted
`December 16, 2003.
`
`Supported by Watson Pharmaceuticals
`Inc.
`
`Authors’ disclosures of potential con-
`flicts of interest are found at the end of
`this article.
`
`Address reprint requests to Michael
`Auerbach, MD, FACP, 9110 Philadel-
`phia Rd, Suite 314, Baltimore, MD
`21237; e-mail: mauerbachmd@aol.com.
`
`© 2004 by American Society of Clinical
`Oncology
`
`0732-183X/04/2207-1301/$20.00
`
`DOI: 10.1200/JCO.2004.08.119
`
`Intravenous Iron Optimizes the Response to
`Recombinant Human Erythropoietin in Cancer Patients
`With Chemotherapy-Related Anemia: A Multicenter,
`Open-Label, Randomized Trial
`Michael Auerbach, Harold Ballard, J. Richard Trout, Marilyn McIlwain, Alan Ackerman,
`Huzefa Bahrain, Stefan Balan, Lance Barker, and Jeevindra Rana
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`Recombinant human erythropoietin (rHuEPO) is the standard of care for patients with chemotherapy-
`related anemia.
`Intravenous (IV)
`iron improves hemoglobin (Hb) response and decreases dosage
`requirements in patients with anemia of kidney disease, but its effect has not been studied in
`randomized trials in cancer patients.
`
`Methods
`This prospective, multicenter, open-label, randomized trial enrolled 157 patients with chemotherapy-
`related anemia (Hb ⱕ 105 g/L, serum ferritin ⱕ 450 pmol/L or ⱕ 675 pmol/L with transferrin saturation
`ⱕ 19%) receiving subcutaneously rHuEPO 40,000 U once weekly to: (1) no-iron; (2) oral iron 325 mg
`twice daily; (3) iron dextran repeated 100mg IV bolus; or (4) iron dextran total dose infusion (TDI). Hb and
`quality of life (QOL) were measured at baseline and throughout.
`
`Results
`All groups showed Hb (P ⬍ .0001) increases from baseline. Mean Hb increases for both IV iron groups
`were greater (P ⬍ .02) than for no-iron and oral
`iron groups. The percentage of patients with
`hematopoietic responses was higher (P ⬍ .01) in both IV iron groups (each case 68%) compared with
`no-iron (25%) and oral iron (36%) groups. IV iron groups showed increases in energy, activity, and overall
`QOL from baseline, compared with a decrease in energy and activity for no-iron group and no change
`in activity or overall QOL for oral iron group.
`
`Conclusion
`rHuEPO increases Hb levels and improves QOL in patients with chemotherapy-related anemia.
`Magnitude of Hb increase and QOL improvement is significantly greater if IV iron is added.
`
`J Clin Oncol 22:1301-1307. © 2004 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Anemia is now recognized as a significant
`consequence of cancer and chemotherapy.
`Chemotherapy-related
`anemia most
`closely resembles the anemia of chronic
`disease, with patients exhibiting serum
`erythropoietin levels that are elevated
`above normal but not as high as those
`demonstrated in patients with similar he-
`moglobin (Hb) decreases caused by iron-
`deficiency anemia or hemolytic anemia.1
`It appears that patients with cancer expe-
`rience a blunted erythropoietin response
`
`to anemia,1 in addition to inadequate
`erythropoietin production.2
`Prospective clinical trials have deter-
`mined that mild-to-moderate anemia oc-
`curs in up to 75% of cancer patients under-
`going treatment with chemotherapy and/or
`radiation therapy.3-5 Data from several
`large, prospective, multicenter, clinical trials
`have shown that recombinant human eryth-
`ropoietin alfa (rHuEPO; PROCRIT; Ortho
`Biotech Products, Bridgewater, NJ) 10,000
`U to 20,000 U or 150 U/kg to 300 U/kg
`administered three times weekly or 40,000 U
`to 60,000 U once weekly increases Hb levels,
`
`1301
`
`Pharmacosmos, Exh. 1011, p. 1
`
`

`
`Auerbach et al
`
`decreases transfusion requirements, and improves quality of
`life (QOL) in anemic cancer patients receiving platinum or
`nonplatinum chemotherapy,
`independent
`of
`tumor
`response,6-9 as well as in patients with cancer-related anemia
`who are not yet receiving chemotherapy.10 Data also suggest
`that rHuEPO administration improves health-related QOL
`and may improve survival in this population.9,11,12
`Thus, rHuEPO therapy has been established as a main-
`stay of care for chemotherapy-related anemia.6-9,13 How-
`ever, approximately 30% to 50% of cancer patients with
`chemotherapy-related anemia do not achieve a meaningful
`response to rHuEPO (a 20-g/L increase in Hb or achieving a
`Hb level of 120 g/L without transfusion use).6-9 Further,
`hematopoietic responses to rHuEPO are not rapid. Many
`patients do not begin to exhibit an increase in Hb level until
`after 4 to 6 weeks of rHuEPO therapy.6-9 Intravenous (IV)
`(but not oral) iron supplementation has been shown to
`improve Hb response to rHuEPO, and to decrease rHuEPO
`dose requirements,
`in patients with anemia related to
`chronic kidney disease (CKD).14-16 Despite these findings,
`clinicians have been reluctant to prescribe IV iron routinely
`for cancer patients with chemotherapy-related anemia, pri-
`marily because of the risk of anaphylaxis associated with
`iron dextran.17 However, this is a relatively rare occurrence.
`The incidence rate of severe reactions was reported as 0.6%
`to 0.7% in hemodialysis patients receiving iron dextran.18
`Because the effect of iron and its route of administration
`have not been studied in randomized trials in the anemic
`cancer population, the purpose of this study was to evaluate
`the effect of iron therapy and its optimal route of adminis-
`tration in cancer patients with chemotherapy-related ane-
`mia who were concomitantly receiving rHuEPO.
`
`METHODS
`
`Participants
`Participants were recruited from the Franklin Square Hospi-
`tal Center, Baltimore, MD; Carillion Oncology Associates,
`Roanoke, VA; Washington Hospital Center, Washington, DC; and
`the New York Harbor Healthcare System, New York, NY. Eligible
`patients had a histologic diagnosis of cancer, an Hb level ⱕ 105
`g/L, and a serum ferritin concentration of ⱕ 450 pmol/L, or ⱕ
`675 pmol/L in concert with a transferrin saturation (TSAT) of
`ⱕ 19%. Eligible patients were also required to have an Eastern
`Cooperative Oncology Group performance status ⱕ 2, a life
`expectancy of at least 6 weeks, and be scheduled to undergo
`chemotherapy while on study.
`Patients with anemia attributable to factors other than cancer
`or chemotherapy (ie, B12, or folate deficiency; hemolysis; gastro-
`intestinal bleeding; or myelodysplastic syndromes) were not eligi-
`ble to participate in the study. Other exclusion criteria included
`prior transfusion, previous iron dextran therapy, allergy or intol-
`erance to rHuEPO, rHuEPO within 4 weeks of enrollment, uncon-
`trolled hypertension, active infection, prior gastric surgery, and
`primary bone marrow malignancy or lymphoma metastatic to the
`bone marrow. Patients with chronic lymphocytic leukemia and
`multiple myeloma were permitted.
`
`Protocol
`This was a prospective, multicenter, open-label, randomized,
`controlled study. The protocol and informed consent were ap-
`proved by the Human Studies Committee and the Institutional
`Review Board at all participating sites. All patients underwent an
`initial screen within 7 days of enrollment. Baseline information
`included patient characteristics, tumor site, and current chemo-
`therapy regimen. Baseline laboratory tests included complete
`blood count, chemical profile, serum iron levels, total iron binding
`capacity, and serum ferritin level. Participants were then randomly
`assigned into four treatment groups: (1) no iron, (2) oral iron
`(ferrous sulfate) 325 mg twice daily, (3) iron dextran 100mg IV
`bolus at each visit to the calculated dose for iron replacement, and
`(4) total dose infusion (TDI) of iron dextran. Patients were fol-
`lowed for 6 weeks, except for those in the bolus arm, who were
`followed until the end of their treatment course. All patients
`provided written informed consent before study participation.
`Patient compliance in group 2 (oral iron) was monitored by
`weekly telephone interviews. For patients in treatment groups 3 or
`4, the total dose of iron dextran was calculated using the following
`formula to reach a desired Hb level of 140 g/L: dose (mL) ⫽ 0.0442
`(desired Hb – observed Hb) x LBW ⫹ (0.26 ⫻ LBW)19 where LBW
`is the patient’s lean body weight in kilograms.
`Patients randomly assigned to 100mg bolus injections re-
`ceived a 25mg test dose of iron dextran by IV push over 1 to 2
`minutes, followed by a 75mg bolus injection, before the first three
`epoetin alfa doses (ie, for the first 3 weeks of the study). Subse-
`quent iron dextran bolus injections did not require a test dose,
`provided that the patient did not demonstrate any allergic reaction
`to the formulation. Participants randomly assigned to TDI
`received methylprednisolone 125 mg before and following the
`infusion, which has been shown to ameliorate the arthralgias and
`myalgias associated with this method of iron dextran administra-
`tion.20 Patients then received a 25mg test dose given by IV push.
`One hour after the test dose was administered, patients received
`the calculated total iron dextran dose in 500 mL of 0.9% NaCl
`solution administered at a rate of 175 mL/h. All patients received
`iron dextran as INFeD (Watson Pharmaceuticals, Morristown,
`NJ) except for two patients who received iron dextran as DexFer-
`rum (American Regent Laboratories, Shirley, NY) during a brief
`period when the first formulation was not available.
`All patients received rHuEPO 40,000 U subcutaneously
`weekly; rHuEPO dose escalation or reduction was not permitted,
`so not to confound the iron response data.
`The primary efficacy variable was defined as the change in Hb
`from baseline to end point. For patients who completed the study,
`end point was the maximum Hb level; for all other patients, end
`point was the Hb level at last observation. Hemoglobin levels were
`measured at baseline and weekly throughout the treatment period.
`The secondary efficacy variables included hematopoietic response,
`time to hematopoietic response, and QOL. Hematopoietic re-
`sponse to rHuEPO was defined as an increase in Hb of ⱖ 20 g/L or
`achievement of a Hb level of ⱖ 120 g/L without transfusion use at
`any time point during the study. QOL was measured at baseline
`and weekly during the study using the 100-mm linear analog scale
`assessment (LASA) of energy level, ability to perform daily activi-
`ties, and overall QOL. This instrument has been validated in the
`cancer population,7 and recent studies have demonstrated a posi-
`tive correlation between LASA and other validated QOL self-
`report instruments (ie, Functional Assessment in Cancer Therapy–
`Anemia subscale).7 Patients were not aware of their hemoglobin
`
`1302
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Pharmacosmos, Exh. 1011, p. 2
`
`

`
`IV Iron Optimizes Response to rHuEPO
`
`levels at the time QOL assessments were made or at any other
`time throughout the study. Treatment-related adverse events
`were recorded weekly. Arthralgia/myalgia syndrome associated
`with TDI was graded according to the criteria of Auerbach et
`al.21 Oral iron compliance was tracked weekly by investigator
`query.
`
`Statistical Analysis
`The number of patients planned for study enrollment was
`based on previous data15 indicating that the interpatient SD for
`Hb, the primary efficacy variable, was 15 g/L. Assuming a clinically
`important treatment group difference in mean Hb of 10 g/L, a
`power of 80%, and a significance level of 0.05, it was determined
`that 47 patients per group (188 patients total) were required for
`this study. Patients were centrally randomly assigned.
`For quantitative variables, the treatment groups were com-
`pared using analysis of variance or the Kruskal-Wallis test, as
`appropriate. The model used in this analysis allowed treatment
`group comparisons after adjusting for any center differences. Pair-
`wise comparisons among the treatment groups were based on least
`squares means, which were also adjusted for any center differ-
`ences. No adjustment for multiple testing was employed. Within
`each treatment group the significance of the change from baseline
`was based on a paired t-test. Treatment group comparisons asso-
`ciated with categoric variables were made using Fisher’s exact test.
`A nonstatistical analysis of possible prognostic indicators
`included cancer diagnosis (solid tumors v hematologic cancers);
`chemotoxicity (mildly v highly myelotoxic chemotherapy, where
`the latter was defined as chemotherapy for intermediate or high-
`grade lymphoma or adjuvant chemotherapy for breast cancer);
`and disease response (stable disease, responsive disease [a 50%
`decrement in radiographic measurement], progressive disease
`[measurable worsening of disease], or adjuvant chemotherapy).
`For safety data, the intent-to-treat (ITT) population was
`analyzed. This population was defined as all patients who received
`at least one dose of study drug. Treatment-related adverse events
`were documented weekly. Treatment groups were compared with
`respect to incidence of adverse events using Fisher’s exact test.
`For all efficacy analyses, a modified ITT population was ana-
`lyzed. This population was defined as all patients who were ran-
`domly assigned and had at least one postbaseline observation. If a
`patient withdrew before study completion, the last observation
`before withdrawal was used. In addition, for patients who were
`transfused or who were given another therapy before study com-
`pletion, the last observation before that event was used in the
`analysis. Statistical significance was declared if the two-sided
`P value was ⱕ .05.
`
`RESULTS
`
`Study Population
`A total of 157 patients were randomly assigned to re-
`ceive no-iron (n ⫽ 36), oral iron (n ⫽ 43), bolus iron
`dextran (n ⫽ 37), or TDI iron dextran (n ⫽ 41). Although
`the study statistical power calculation had required 188
`patients to be enrolled, the length of time that the study took
`precluded some sites from participating so it was decided to
`close the study before target enrollment was reached. Of the
`157 patients randomly assigned, 155 patients had at least
`one postbaseline Hb value and were included in the modi-
`
`fied ITT population. One hundred thirty-two patients com-
`pleted at least 6 weeks of treatment or all bolus treatments
`per protocol. Of the 25 patients who did not complete the
`protocol, 19 received a transfusion, three were administered
`parenteral iron therapy due to a lack of response to oral or
`no-iron therapy, one experienced a test dose reaction, and
`two died (as a result of causes unrelated to the study).
`Baseline demographics and clinical characteristics were
`similar between the four groups (P ⱖ .13; Table 1). The
`most common cancer diagnoses were lung (27%), gastro-
`intestinal (22%), and breast cancer (18%); 19% of patients
`were diagnosed with hematologic malignancies (Fig 1). All
`patients received chemotherapy during the study. There
`were no significant differences between treatment groups
`by cancer diagnosis, toxicity of prescribed chemotherapy,
`or response to chemotherapy.
`Patients randomly assigned to the bolus IV iron group
`received between 11 and 24 doses of 100mg IV iron (total
`dose range, 1,100 mg to 2,400 mg). Patients randomly as-
`signed to the TDI group received IV iron doses ranging
`
`Table 1. Baseline Clinical Characteristics
`
`Characteristic
`
`Sex
`Male
`No. of Patients
`%
`Female
`No. of Patients
`%
`Age, years
`Mean
`SD
`Hb, g/L
`Mean
`SD
`LASA, mm
`Energy
`Mean
`SD
`Activity
`Mean
`SD
`Overall QOL
`Mean
`SD
`Ferritin pmol/L
`Mean
`SD
`Transferrin saturation, %
`Mean
`SD
`
`No-Iron
`Group
`(n ⫽ 36)
`
`Oral Iron
`Group
`(n ⫽ 43)
`
`Bolus
`Group
`(n ⫽ 37)
`
`TDI
`Group
`(n ⫽ 41) P
`
`19
`53
`
`17
`47
`
`65
`11
`
`95
`9
`
`53
`22
`
`54
`26
`
`57
`26
`
`294
`238
`
`15
`8
`
`29
`67
`
`14
`33
`
`66
`12
`
`97
`7
`
`46
`23
`
`51
`32
`
`55
`28
`
`290
`160
`
`18
`14
`
`18
`49
`
`19
`51
`
`63
`13
`
`97
`8
`
`42
`23
`
`46
`24
`
`50
`25
`
`207
`153
`
`19
`17
`
`.28
`
`.28
`
`.70
`
`.37
`
`.17
`
`.27
`
`.47
`
`.13
`
`.28
`
`26
`63
`
`15
`37
`
`64
`11
`
`94
`10
`
`43
`23
`
`42
`24
`
`49
`23
`
`240
`175
`
`14
`10
`
`Abbreviations: TDI, total dose infusion; SD, standard deviation; LASA,
`Linear Analog Scale Assessment; QOL, quality of life.
`
`www.jco.org
`
`1303
`
`Pharmacosmos, Exh. 1011, p. 3
`
`

`
`Auerbach et al
`
`Fig 1. Cancer diagnoses for enrolled
`patients (n ⫽ 157). Solid tumors, 77%;
`hematologic malignancies, 19%; non-
`hematologic/other, 4%. CLL, chronic
`lymphocytic leukemia; MM, multiple
`myeloma.
`
`from 1,000 mg to 3,000 mg. In the oral iron group, overall
`compliance exceeded 90%.
`Efficacy Evaluations
`Hemoglobin response. All treatment groups showed
`significant (P ⬍ .0001) increases in Hb level from baseline
`(Fig 2). Mean increases were 9 g/L, 15 g/L, 25 g/L, and 24 g/L
`for the no-iron, oral, IV bolus, and TDI groups, respec-
`tively. Mean end point Hb levels were 105 g/L, 112 g/L, 122
`g/L (P ⬍ .05 v no-iron and oral iron groups), and 119 g/L
`(P ⬍ .05 v no-iron group), respectively. Mean Hb increases
`for both IV iron groups were significantly higher than the
`no-iron and oral iron groups (P ⬍ .02). There was no
`significant difference in mean Hb increase between the
`no-iron and oral iron groups (P ⫽ .21) or between the two
`
`IV iron groups (P ⫽ .53). Treatment group differences in
`hemoglobin response seemed to be independent of baseline
`TSAT (⬍ 15% or ⬎ 15%), chemotherapy toxicity (highly
`myelotoxic or mildly myelotoxic regimens), cancer diagno-
`sis (solid or hematologic cancers), or disease response (pro-
`gressive disease, stable disease, responsive disease, or adju-
`vant chemotherapy). In addition, the percentage of patients
`with a hematopoietic response was significantly higher in
`the IV iron groups than in the no-iron and oral-iron groups
`(P ⬍ .01). Sixty-eight percent of patients in each of the TDI
`and IV bolus groups achieved a hematopoietic response (at
`5.0 ⫾ 1.0 and 9.7 ⫾ 3.3 weeks, respectively) compared with
`25% of patients in the no-iron group and 36% of patients in
`the oral iron group (at 4.2 ⫾ 1.6 and 5.2 ⫾ 0.9 weeks,
`respectively; Fig 3).
`
`Fig 2. Hb changes from baseline to end point by treatment group for the
`ITT population. Difference from baseline to end point Hb value, P ⬍ .001 for
`all treatment groups. a, P ⬍ .05 v no-iron group; b, P ⬍ .05 v oral iron group.
`
`Fig 3. Percentage of responders and nonresponders in each treatment
`group for the ITT population. Responders were patients who achieved a
`maximal Hb levels ⱖ 120 g/L or an increase in Hb of ⱖ 20 g/L during the
`study. a P ⬍ .01 v no-iron group; b P ⬍ .01 v oral iron group.
`
`1304
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Pharmacosmos, Exh. 1011, p. 4
`
`

`
`IV Iron Optimizes Response to rHuEPO
`
`after initiation of therapy were considered treatment fail-
`ures in the ITT analysis. Nineteen of these patients received
`transfusions (seven patients in the no-iron group, three
`patients in the oral iron group, four patients in the IV bolus
`iron group, and five patients in the TDI iron group; P ⫽ not
`significant). Three patients from no-iron (n ⫽ 2) or oral
`iron (n ⫽ 1) groups were given parenteral iron therapy.
`Two of these patients showed improvements in Hb level
`(101 g/L to 107 g/L and 100 g/L to 116 g/L). The third
`patient required a transfusion 2 weeks after parenteral iron
`therapy was administered. For these 22 patients, study ob-
`servations before transfusion or alternative therapy were
`carried forward and used in the ITT analysis.
`
`Fig 4. Change in LASA scores from baseline to end point evaluation for the
`intent-to-treat population. Qol, quality of life; TDI, total dose infustion.
`
`DISCUSSION
`
`QOL. For energy, activity, and QOL, both IV iron
`groups showed increases in LASA scores from baseline to
`end point (Fig 4). For patients who completed the study,
`end point was defined as the time that maximum Hb was
`achieved. For all other patients, the end point was defined as
`the last observation. With the exception of the bolus group
`end point was no longer than 6 weeks. Conversely, the
`no-iron group showed small decreases in energy, activity
`and QOL scores compared with baseline. Although the oral
`iron group had an increase in energy from baseline, this
`group had only small changes from baseline in activity or
`overall QOL. For each of these three parameters, mean
`increases were observed in the IV iron groups that were
`greater than those of the no-iron and oral iron groups. When
`the data for all of the treatment groups were pooled, there was
`a significant correlation between increase in Hb and improve-
`ments in energy (r ⫽ 0.32, P ⬍ .0001), activity (r ⫽ 0.30, P ⫽
`.0002), and overall QOL (r ⫽ 0.31, P ⫽ .0001).
`Safety. Seven patients experienced adverse events that,
`in the opinion of the investigator, were related to treatment.
`Three (7%) of 41 patients in the TDI group experienced an
`adverse event: delayed arthralgia/myalgia syndrome (two
`events, grade 1), or acute hypersensitivity reaction (one
`event). Three (8%) of 37 patients in the bolus group expe-
`rienced the following adverse events: delayed arthralgia/
`myalgia syndrome (one event, grade 2), fatigue (one event),
`or shortness of breath (one event). One (2%) of 43 patients
`in the oral iron group experienced nausea (one event). The
`acute hypersensitivity reaction comprised chest/back pain,
`nausea, vomiting, flushing, and hypotension; it occurred
`with a test dose (iron dextran as DexFerrum) and precluded
`further therapy. This event subsequently resolved com-
`pletely with no residual effects. Two deaths unrelated to
`study drug were reported; one patient in the oral iron group
`and one patient in the TDI group died during the study
`period due to disease progression.
`Transfusions and treatment failures. The 22 patients
`who experienced a clinically significant decrease in Hb level
`
`The results of this randomized study demonstrate that
`rHuEPO increases Hb levels in the absence of iron supple-
`mentation or in the presence of oral iron supplementation
`in cancer patients with chemotherapy-related anemia. In
`addition, Hb increases were associated with measurable
`improvements in QOL over the study period, as has been
`reported in many previous studies.6-9 Our study is unique
`in that it further demonstrates that the magnitude of the Hb
`increase resulting from rHuEPO treatment is significantly
`greater if IV iron is added to the therapeutic regimen, com-
`pared with oral iron supplementation. In addition, a mean
`Hb increase of more than 20 g/L was achieved after only 6
`weeks of rHuEPO plus IV iron therapy in this study
`whereas, typically, studies have reported this level of Hb
`increase after 8 weeks or more of rHuEPO treatment. Pre-
`vious studies have shown that increases in Hb as small as
`10g/L are clinically significant.6,9 The percentage of re-
`sponders in the IV iron groups (68%) was similar to rates
`reported in studies using rHuEPO once weekly or three
`times weekly for 12 weeks or more (49% to 71%).6-9 Re-
`sponders were defined as achieving an increase in Hb of ⱖ
`20 g/L or an Hb level of ⱖ 120 g/L, without transfusion use,
`at any time point during the study. Our results indicate that
`iron supplementation by the IV route provides the most
`optimal environment for augmenting erythropoiesis and
`improving QOL domains. Although methylprednisolone
`may have a positive effect on QOL variables, the absence of
`differences between the bolus (no methylprednisolone
`given) and TDI groups indicates methylprednisolone was
`not a factor. These findings have important implications for
`optimizing rHuEPO therapy in the oncology setting and for
`the cost-effectiveness of this treatment. IV iron represents a
`new strategy and treatment modality for optimizing the
`efficacy of rHuEPO in the management of patients with
`anemia related to cancer and its treatment.
`Despite its demonstrated efficacy, approximately 30%
`to 50% of patients do not exhibit a meaningful response to
`rHuEPO therapy in clinical trials of 12 to 24 weeks in
`
`www.jco.org
`
`1305
`
`Pharmacosmos, Exh. 1011, p. 5
`
`

`
`Auerbach et al
`
`duration,6-9 and iron deficiency appears to be a major de-
`terminant for the efficacy of rHuEPO therapy. Data from
`the dialysis population has clearly shown that the most
`important reason for hyporesponsiveness to rHuEPO in
`clinical practice is failure to provide sufficient iron supple-
`mentation.14,15 During rHuEPO administration,
`large
`amounts of iron are required to keep pace with the demands
`of rHuEPO-stimulated erythropoiesis. Persistent anemia in
`many nonresponders may result from a functional iron
`deficiency that occurs in concert with the rapid initiation of
`erythropoiesis stimulated by rHuEPO.22 Patients with
`functional
`iron deficiency cannot supply iron quickly
`enough to meet the demands of rHuEPO-induced erythro-
`poiesis, despite having adequate iron stores.17 In contrast,
`patients with absolute iron deficiency have inadequate iron
`stores (TSAT ⬍ 20%, serum ferritin ⬍ 224.7 pmol/L).22
`Functional iron deficiency in this setting is consistent with the
`theory that iron supply to the erythron becomes the rate-
`limiting step in erythropoiesis. Therefore, despite an adequate
`iron store, iron supplementation may still be required to
`achieve or maintain an optimal response to rHuEPO.
`The iron required by RBCs in the bone marrow is
`supplied by the usable iron pool in the reticuloendothelial
`system, which is in balance with iron stores also found in the
`reticuloendothelial system.22 RBC production initiated by
`rHuEPO can surpass the rate of iron mobilization from
`stores to the usable iron pool, even in the presence of
`adequate iron stores.22 In addition, inflammatory cytokines
`observed in patients with the anemia of chronic disease may
`hinder release of stored iron, further limiting the rate of
`RBC production.2 Combined, these factors can lead to a
`rapid depletion of the usable iron pool, delaying the re-
`sponse to rHuEPO.
`A key issue for maximizing rHuEPO therapy is the
`appropriate method for providing iron supplementation.
`In patients with CKD, studies have demonstrated that oral
`iron supplementation does not provide iron quickly
`enough to support the accelerated erythropoiesis that oc-
`curs with rHuEPO therapy.14,15,23 In addition, intolerable
`gastrointestinal side effects have been reported with the
`high-doses of oral iron required in this setting,14 and three-
`times-daily dosing of oral iron also is necessary, both of
`which are likely to lead to patient noncompliance.22 More-
`over, oral iron administration is associated with impaired
`gastrointestinal absorption.24 The inadequate response to
`oral iron therapy observed in our 6-week study mirrors
`these findings and suggests that oral iron supplementation
`should not be considered the optimal route of administra-
`tion for patients with anemia of cancer and its treatment.
`The ITT study design addresses the issue of noncompliance
`with oral iron in the clinical setting.
`Compared with oral iron, IV iron appears to ade-
`quately support erythropoiesis during rHuEPO therapy by
`supplying sufficient iron quantities at the rate needed. Our
`
`data support those from patients with CKD showing that
`poor response to rHuEPO can be enhanced by IV iron
`administration, and that the efficacy of oral iron was similar
`to that of no-iron.14,15 In the CKD population, IV iron
`therapy has been shown to decrease the rHuEPO dose
`needed to ameliorate anemia, which increases the cost-
`effectiveness of the drug.14
`Although adverse events related to IV iron dextran
`therapy may be of concern to clinicians, the safety of IV iron
`dextran has been well documented in patients with CKD-
`related anemia, with a 0.7% incidence of severe adverse
`reactions in 573 patients receiving the INFeD formulation
`of iron dextran.18,22 Moreover, newer, nondextran iron
`preparations, not yet approved by the US Food and Drug
`Administration for use in oncology patients, may have an
`improved safety profile and are worthy of further study.25,26
`In our study, adverse events were few and did not require
`discontinuation of therapy. In a single instance, therapy had
`to be interrupted because of an acute hypersensitivity reaction
`to IV iron dextran, which subsequently resolved without resid-
`ual effects. This patient was one of the two patients who re-
`ceived the DexFerrum formulation of iron dextran during a
`period when the INFeD formulation was unavailable.
`A recent publication raised concerns about the safety of
`erythropoietin therapy.27 The authors stated that in pa-
`tients with head and neck cancer undergoing radiation
`therapy erythropoietin beta therapy might be associated
`with unfavorable outcomes. Although these findings may
`not be generalizable to patients treated with chemotherapy
`or with other erythropoietic agents, they suggest that future
`trials should consider measuring the impact of erythropoi-
`etic therapy on cancer control and survival. Our study
`looked at a broader range of tumor types in patients treated
`with chemotherapy rather than radiation therapy. A differ-
`ent erythropoietic agent was used, and our study was not
`designed both in longevity and power to assess cancer out-
`come and survival.
`Although this study was not statistically powered to
`detect differences between functional and absolute iron
`deficiency, the results suggest that correcting functional, as
`well as absolute, iron deficiency with IV iron supplementa-
`tion will improve the response to rHuEPO therapy of pa-
`tients with anemia related to cancer. In the absence of data
`identifying significant predictors of response to rHuEPO
`therapy in cancer-related anemia, a more aggressive treat-
`ment paradigm that includes IV iron supplementation
`should become an integral and routine component of
`rHuEPO therapy in this population, as it has in patients with
`CKD-related anemia. As clinicians gain a better understanding
`of the concept of functional iron deficiency, it is clear that IV
`iron therapy is critical for optimizing the response to rHuEPO
`treatment for chemotherapy-related anemia.
`
`I I I
`
`1306
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Pharmacosmos, Exh. 1011, p. 6
`
`

`
`IV Iron Optimizes Response to rHuEPO
`
`Acknowledgment
`We thank Naomi Dahl for her technical assistance dur-
`ing the development of this manuscript.
`
`Authors’ Disclosures of Potential
`Conflicts of Interest
`The following authors or their immediate family mem-
`bers have indicated a financial interest. No conflict exists for
`
`drugs or devices used in a study if they are not being evalu-
`ated as part of the investigation. Acted as a consultant
`within the last 2 years: Michael Auerbach, Watson Pharma-
`ceuticals; J. Richard Trout, Watson Pharmaceuticals. Re-
`ceived more than $2,000 a year from a company for either of
`the last 2 years: Michael Auerbach, Watson Pharmaceuti-
`cals; J. Richard Trout, Watson Pharmaceuticals; Marilyn
`McIlwain, Watson Pharmaceuticals.
`
`REFERENCES
`
`1. Miller CB, Jones RJ, Piantadosi S, et al:
`Decreased erythropoietin response in patients
`with the anemia of cancer. N Engl J Med 322:
`1689-1692, 1990
`2. Means RT Jr, Krantz SB: Progress in un-
`derstanding the pathogenesis of the anemia of
`chronic disease. Blood 80:1639-1647, 1992
`Itri LM: Chemotherapy-
`3. Groopman JE,
`induced anemia in adults: Incidence and treat-
`ment. J Natl Cancer Inst 91:1616-1634, 1999
`4. Birgegard G, Ludwig H, Nortier JWR, et al:
`Despite high prevalence of anemia and impact
`on performance status (PS), anemia treatment
`(Tx) rate is low in multiple myeloma/lymphoma
`(MM/L) patients (pts) according to European
`Cancer Anaemia Survey (ECAS). Blood 100:18b,
`2002 (abstr 3521)
`5. Ludwig H, Birgegard G, Barrett-Lee P, et
`al: Prevalence and management of anemia in
`patients (pts) with hematologic malignancies
`(HMs) and solid tumors (STs): results from the
`European Cancer Anaemia Survey (ECAS). Blood
`100:234a-235a, 2002 (abstr 884)
`6. Glaspy J, Bukowski R, Steinberg D, et al:
`Impact of therapy with epoetin alfa on clinical
`outcomes in patients with nonmyeloid malignan-
`cies during cancer chemotherapy in community
`oncology practice: Procrit Study Group. J Clin
`Oncol 15:1218-1234, 1997
`7. Demetri GD, Kris M, Wade J, et al:
`Quality-of-life benefit in chemotherapy patients
`treated with epoetin alfa is independent of dis-
`ease response or tumor type: Results from a
`prospective community oncology study—Procrit
`Study Group. J Clin Oncol 16:3412-3425, 1998
`8. Gabrilove JL, Cleeland CS, Livingston RB,
`et al: Clinical evaluation of once weekly dosing of
`epoetin alfa in chemotherapy patients: Improve-
`ments in hemoglobin and quality of life are
`similar to three-times-weekly dosing. J Clin On-
`col 19:2875-2882, 2001
`9. Littlewood TJ, Bagetta E, Nortier JWR, et
`al: Effects of epoetin alfa on hematologic param-
`
`eters and quality of life in cancer patients receiv-
`ing nonplatinum chemotherapy: Results of a
`randomized, double-blind, placebo-controlled
`trial. J Clin Oncol 19:2865-2874, 2001
`10. Quirt I, Robeson C, Lau