This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hudis, C. A. Articles by Muenstedt, K. Search for Related Content PubMed PubMed Citation Articles by Hudis, C. A. Articles by Muenstedt, K.

rHuEPO and Treatment Outcomes: the Clinical Experience

^a Memorial Sloan-Kettering Cancer Center, New York, New York, USA; ^b University Hospital Ghent, Ghent, Belgium; ^c Durham Regional Cancer Centre, Oshawa, Ontario, Canada; ^d Justus-Liebig-University of Giessen, Giessen, Germany

Correspondence: Clifford A. Hudis, M.D., Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-5449; Fax: 212-639-6483; e-mail: hudisc{at}mskcc.org

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
After completing this course, the reader will be able to:

1. Relate anemia to treatment outcome in a number of solid tumors.
   
2. Relate hemoglobin level to quality of life.
   
3. Describe the potential adverse consequences of overtreating anemia.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
Increasingly, anemia is being recognized as a negative prognostic and predictive factor for patients undergoing chemotherapy, radiation therapy, or a combination of these treatment modalities. The results of clinical studies have shown correlations between anemia and shorter survival times in patients with a wide variety of solid tumors and hematologic malignancies, including lung, ovarian, breast, and head/neck cancers, non-Hodgkin’s lymphoma, Hodgkin’s disease, Waldenström’s macroglobulinemia, and chronic lymphocytic leukemia. Also, anemia has been shown to predict treatment response in patients with ovarian, cervical, and urothelial cancers, mantle cell lymphoma, and chronic lymphocytic leukemia, as well as refractory/relapsed acute myelogenous leukemia. Based on the presumed causal relationship between anemia and poor patient outcome, several studies have examined the influence of epoetin alfa (a recombinant human erythropoietin) on outcomes in anemic patients undergoing cancer treatment. The results of these studies have been encouraging, with indications of greater locoregional tumor control and higher response rates in epoetin alfa-treated patients. Additionally, epoetin alfa therapy, by correcting anemia, has been shown to improve a patient’s energy level, ability to perform daily activities, and overall quality of life (QOL). Such effects not only enhance a patient’s general well-being, but may also increase their tolerance of, and willingness to undergo, full courses of their cancer therapy in a timely manner. These findings support the use of epoetin alfa to achieve gains in QOL and cancer treatment outcomes in anemic cancer patients and suggest that additional studies be conducted to further investigate the potential benefits of this agent in regard to improved outcomes.

Key Words. Anemia • Cancer • Epoetin alfa • Hemoglobin • Outcomes • Quality of life • rHuEPO • Survival • Tumor hypoxia

	INTRODUCTION

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
Because of recent advances in treatment, more cancer patients are cured than in the past, and many with incurable disease are living longer. Thus, although the main goal of cancer treatment—disease cure—remains unchanged, greater attention is now being focused on treatment goals relevant to improved survivorship, including prolongation of life, symptom palliation, and improvement or preservation of quality of life (QOL) during and after cancer therapy.

Where cure is not achievable, the outcomes of cancer therapy are typically measured in terms of overall survival, disease-free survival, progression-free survival, response rate, and QOL. These outcomes are influenced by various baseline characteristics related to the patient (e.g., age, sex, performance score) and the malignancy (e.g., histologic subtype, disease stage), as well as by disease-targeted and supportive therapy. Often, it is possible to identify baseline characteristics as having prognostic or predictive significance. Prognostic factors are variables that independently influence outcome, whereas predictive factors are those that independently affect response to treatment. Because prognostic factors suggest the future course of the disease, they can be helpful in developing treatment strategies. Patients considered high risk on the basis of these factors may, thus, be targeted for more aggressive or experimental regimens, whereas lower-risk patients may be considered for less aggressive therapy, thereby avoiding severe or serious side effects.

One factor known to cause a wide range of symptoms and impairments in cancer patients is anemia, a complication of both the disease and its treatment. The symptoms of anemia, particularly fatigue, can adversely affect a patient’s QOL and may even diminish the patient’s tolerance of, and willingness to undergo, cancer treatment. However, emerging evidence over the past decade has suggested that anemia may additionally be related to poor clinical outcomes, including survival. Results of a meta-analysis performed by Caro et al. [1] indicated an overall estimated 65% greater relative risk of death in anemic cancer patients, compared with nonanemic patients. One possible explanation for this effect may be that anemia plays a role in the development of tumor hypoxia. Studies have shown that tumor hypoxia contributes to a number of processes that culminate in resistance to sparsely ionizing radiation and oxygen-dependent chemotherapeutic agents, and that improving the oxygenation of hypoxic tumor tissue may improve tumor responsiveness to these treatment modalities [2]. Because of the apparent interconnections among anemia, hypoxia, tumor responsiveness to therapy, and outcomes, clinical studies have been conducted to assess the importance of hemoglobin (Hb) level as a prognostic and predictive factor, as well as the impact of increasing Hb levels on patient outcomes. The findings of a representative group of these studies are summarized here. Collectively, the results of these studies suggest that Hb level may, in fact, influence outcome, which could have important implications for the development of management strategies for cancer patients.

	HEMOGLOBIN AS A PROGNOSTIC AND PREDICTIVE FACTOR IN CANCER

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
The importance of Hb level as a prognostic and predictive factor for outcome has been examined both in patients with solid tumors and in those with hematologic malignancies. The findings of those studies are generally consistent across the two tumor classes, with nearly all univariate and multivariate analyses demonstrating a low Hb level to be a negative prognostic or predictive indicator of overall survival and other measures of outcome following cancer therapy. The results of many of these studies have been extensively reviewed by Harrison et al. [3] and, more recently, by Van Belle and Cocquyt [4].

In a series of 17 studies of solid tumors conducted between 1991 and 2003, a low Hb level was found to be prognostic for overall survival in patients with lung, ovarian, renal, pancreatic, and head/neck cancers, and predictive for treatment failure in patients with cervical cancer and for treatment response in patients with ovarian and urothelial cancer (Table 1). In another series, which comprised 10 studies of hematologic malignancies conducted between 1998 and 2000, low Hb level proved prognostic for overall survival in patients with non-Hodgkin’s lymphoma, follicular lymphoma, mantle cell lymphoma, Hodgkin’s disease, and chronic lymphocytic leukemia, and predictive for response in mantle cell lymphoma and chronic lymphocytic leukemia (Table 2). In the majority of these studies, the patients had been treated with chemotherapy, although chemoradiotherapy or radiation therapy had been administered in a small proportion of the studies. The Hb level associated with poor outcome varied among the studies, ranging from 10.5–12.0 g/dl.

In another recent study, Sevelda et al. [7] evaluated the influence of anemia on local relapse-free survival in 424 premenopausal patients with Stage I or II primary breast cancer and hormone-responsive tumors who were undergoing adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. The study was a prospective, randomized, phase III trial; however, the influence of anemia was determined by retrospective analysis of the prospectively collected data. Anemia developed in 77 of the 424 patients (18.2%) during CMF therapy. After a median follow-up period of 5 years, 8.9% of the patients without anemia had experienced a local relapse, compared with 19.6% of those with anemia (p = 0.0006, log-rank test). Multivariate analysis of established prognostic factors showed that only anemia, age, and axillary lymph node status were independent significant prognostic factors for local relapse-free survival.

A small study reported in early 2003 by Morganti et al. [8] evaluated the impact of pretreatment Hb level on outcome in patients with locally advanced pancreatic carcinoma treated with chemoradiation. Thirty patients undergoing concomitant chemoradiation and external beam radiotherapy were divided into two groups based on the pretreatment median Hb level (11.5 g/dl; range: 9.6–15.0 g/dl). The median metastasis-free survival time was 5.1 months for patients with pretreatment Hb levels 11.5 g/dl and was 10.7 months for patients with pretreatment Hb levels >11.5 g/dl (p = 0.010). The median actuarial disease-free survival times were 5.1 months and 10.2 months for patients with pretreatment Hb levels 11.5 g/dl and >11.5 g/dl, respectively (p = 0.026); median actual overall survival times were 7.5 months and 10.3 months for patients with pretreatment Hb levels 11.5 g/dl and >11.5 g/dl, respectively (p = 0.039). Multivariate analysis showed Hb concentration at diagnosis to be the only factor positively correlated with metastasis-free survival (p = 0.026), disease-free survival (p = 0.032), and overall survival (p = 0.048).

Harrison et al. [3], in their 2002 publication, reviewed the prognostic significance of pretreatment anemia in 12 studies of patients with cervical or head/neck cancer who underwent radiation therapy between 1995 and 1999. As in the previous series, the results were generally highly consistent across the studies, with most univariate and multivariate analyses demonstrating that low pretreatment Hb level is a significant prognostic indicator of disease control and survival following curative-intent radiation therapy. The Hb values associated with poor outcome in those studies ranged from <14.5 g/dl for males and <13.0 g/dl for females to <10.0 g/dl. Importantly, Harrison et al. noted findings in about half the studies suggested that the Hb threshold in the radiation oncology setting should be within the range of 12–14 g/dl. This recommendation is consistent with that of Grogan et al. [9], who stressed the importance of correcting anemia and maintaining Hb level above 12 g/dl to maximize the efficacy of radiation therapy (see below). Additionally, Harrison et al. indicated that low intratreatment Hb level, although not as extensively studied as low pretreatment Hb level, also appeared to adversely affect radiation therapy outcomes in patients with cervical or head/neck cancer.

	INCREASED HB AND TREATMENT OUTCOME

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
Based on the theorized causal relationship between anemia/low Hb level and poorer outcome, several recent studies have evaluated the impact of increasing Hb level on patient outcomes following radiation therapy, chemotherapy, or radiochemotherapy. In those studies, Hb levels were increased either by blood transfusion [9, 10] or by the administration of epoetin alfa [11–15] or epoetin beta [16].

Grogan et al. demonstrated the importance of Hb level and blood transfusion during radiation therapy with respect to survival in patients with cervical cancer [9, 10]. In that study, data on Hb levels, blood transfusions, and outcomes were collected retrospectively for patients who received radiation therapy during 1989, 1990, and 1992 in seven Canadian institutions. Those years were specifically selected to allow examination of the impact of changes in transfusion usage over that period, as well as adequate follow-up time. In all, 605 patients who had been followed for a median of 41 months (51 months for survivors) were included in the analyses. Sixty-nine patients (11%) had received chemotherapy in addition to radiation therapy; 152 patients (25%) had received transfusions during cancer treatment, most frequently when their Hb levels were below 10.0 g/dl. Results of a univariate analysis showed that a baseline Hb level 12.0 g/dl (versus an Hb level <12.0 g/dl) was associated with higher rates of pelvic disease control (p = 0.002) and disease-free survival (p = 0.005). On multivariate analysis, baseline Hb level was no longer a significant prognostic factor, but the average weekly nadir Hb level (AWNH) was shown to significantly predict outcome and was second only to disease stage as a prognostic factor. Analyses were conducted to evaluate the importance of increasing the Hb level during radiotherapy, which at the time of the study (1989, 1990, and 1992) was accomplished by blood transfusion. As shown in Figure 1, the 5-year survival rate for patients who had low (<12.0 g/dl) baseline Hb levels that remained low (L-L) was 51% versus 70% for patients with low baseline Hb levels that increased to high (12.0 g/dl) (L-H). The 5-year survival rate for patients with high baseline Hb levels that remained high (H-H) was 74%, with the worst survival rate shown for patients with high baseline Hb levels that decreased during treatment (H-L). Differences in survival rates were significant on multivariate analysis (p < 0.0002). Significant differences were also seen among these patient groups for rates of overall relapse (~56% [L-L] versus 32% [L-H] and 33% [H-H]; p = 0.001), local recurrence (~42% [L-L] versus 24% [L-H] and 22% [H-H]; p = 0.008), and distant metastasis (33% [L-L] versus 12% [L-H] and 23% [H-H]; p = 0.02). Multivariate analysis additionally showed a significant (p < 0.0001) stepwise increase in survival rate with increasing AWNH, with no survival difference between patients whose Hb levels were attained via transfusion and those whose Hb levels were achieved spontaneously. Based on these findings, the investigators theorized that amelioration of anemia and maintenance of Hb level above 12.0 g/dl were vital to successful radiation therapy.

View larger version (12K): [in this window] [in a new window]   Figure 1. Five-year survival according to Hb level (high: 12.0 g/dl or low: <12.0 g/dl) at baseline and during radiotherapy. Patients with low baseline Hb levels that were corrected with blood transfusions (L-H) had a similar 5-year survival rate as patients with high baseline Hb levels that remained high (H-H). Patients with high baseline Hb levels that dropped during therapy (H-L) had a similar 5-year survival rate as patients with low baseline Hb levels that remained low (L-L). The difference among groups was significant (p < 0.0002). Adapted with permission from Grogan et al. [9].

View larger version (22K): [in this window] [in a new window]   Figure 2. Kaplan-Meier estimate of survival at a 26-month median follow-up (i.e., 12 months after completion of study by the last patient). Slashes represent the end of the observation period for surviving patients (p = 0.13, log-rank test). Reprinted with permission from Littlewood et al. [13].

View larger version (15K): [in this window] [in a new window]   Figure 3. Overall survival by pretreatment Hb level and epoetin alfa therapy for patients with squamous cell carcinoma of the oral cavity and oropharynx. *Hb 14.5 g/dl versus Hb <14.5 g/dl and no epoetin alfa. Hb <14.5 g/dl and no epoetin alfa versus Hb <14.5 + epoetin alfa. Adapted with permission from Glaser et al. [12].

View larger version (9K): [in this window] [in a new window]   Figure 4. Response rate in 25 patients with Rai stage III B-chronic lymphocytic leukemia treated with rHuEPO (3-month induction: 150 IU/kg s.c. three times weekly up to 300 IU/kg after 1 month, if response was inadequate; maintenance: 150 IU/kg s.c. once weekly, continuously) [15].

	INCREASED HB LEVEL AND QOL

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
With the higher cure rates and longer durations of survival now being achieved in cancer patients, maintenance or improvement in patients’ QOL is increasingly being perceived as an important and worthwhile goal of cancer management. A growing body of evidence suggests that anemia is strongly related, possibly in a causative manner, to diminished QOL in cancer patients. The symptoms of anemia, such as dyspnea, weakness, tachycardia, impaired cognitive function, depression, and most especially fatigue, can lead to a substantial reduction in functional ability and a decline in general health, thereby contributing to the patient’s feelings of diminished QOL. Recent studies have demonstrated that even mild and moderate anemia (generally characterized as Hb levels of 10–12 g/dl and 8–10 g/dl, respectively) are associated with fatigue and diminished QOL [18–22]. These findings were highlighted by Cleeland et al. [21, 22], who demonstrated a direct relationship between epoetin alfa-induced Hb increases and improvements in QOL in anemic cancer patients. Analyses of data from two open-label, community-based studies of epoetin alfa [23, 24] (see below) that enrolled 4,712 anemic cancer patients showed that the greatest improvement in the patients’ QOL occurred when the Hb level was increased from 11 g/dl to 12 g/dl (range: 11–13 g/dl) [21, 22]. However, given the concerns raised by the prospective randomized trial, this therapeutic approach cannot be considered outside an appropriate clinical trial.

Epoetin alfa has been shown in both double-blind, placebo-controlled and open-label, single-arm studies to increase Hb levels and thereby produce significant improvements in QOL [13, 23–27]. In 1990, the potential advantage of epoetin alfa with respect to QOL was suggested by the findings of Ludwig et al. [25], who administered epoetin alfa to a small group of patients with multiple-myeloma-associated anemia. Not only were the clinical symptoms of anemia ameliorated in those patients who responded to epoetin alfa, but most reported a heightened sense of well-being as well as an increased tolerance of physical exertion, which was reflected by a marked change in performance status as assessed by World Health Organization criteria. A subsequent series of three placebo-controlled studies demonstrated a relationship between epoetin alfa-induced hematopoietic improvement and improvement in QOL as measured using the Linear Analog Scale Assessment (LASA, also referred to as the Cancer Linear Analog Scale or CLAS) [26]. The LASA, which measures the QOL parameters of Energy Level, Ability to Do Daily Activities, and Overall QOL, is a validated, cancer-specific instrument now commonly used to assess therapy-related QOL changes in anemic cancer patients. The populations of anemic cancer patients in the respective studies were: patients not receiving chemotherapy or radiation therapy; patients receiving noncisplatin-containing chemotherapy; and patients receiving chemotherapy containing cisplatin (Platinol^®; Bristol-Myers Squibb). In the study with patients who did not receive cancer therapy, hematocrit level increased by 2.8% from baseline to last value in epoetin alfa-treated patients but decreased by 0.1% in placebo-treated patients. In the noncisplatin study, hematocrit increased by 6.9% in epoetin alfa-treated patients and by 1.2% in placebo-treated patients. The respective values in the cisplatin study were 6.0% and 1.3% (p < 0.004 for each study). Moreover, the QOL parameters Energy Level, Ability to Do Daily Activities, and Overall QOL were improved to a significantly greater extent in patients responding to epoetin alfa than in patients given placebo (p < 0.05 for each parameter).

The impact of increasing Hb level on QOL was demonstrated in three large, community-based, nonrandomized, open-label studies. A collective total of 7,724 patients were enrolled, 7,283 of whom were assessable. In those studies, epoetin alfa was administered to anemic patients with nonmyeloid malignancies undergoing standard chemotherapy. Two of the studies, one conducted by Glaspy et al. [23] and the other by Demetri et al. [24], used three-times weekly dosing, whereas the third study, conducted by Gabrilove et al. [27], used once weekly dosing. QOL measures included the LASA [23, 24, 27], the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale [24], and the FACT-An Anemia subscale [24, 27]. Results of the QOL analyses as assessed by the LASA are summarized in Table 6 [23, 24, 27, 28]. As shown, the scores for the Energy Level, Ability to Do Daily Activities, and Overall QOL items were significantly (p < 0.001) improved from baseline in each study. Importantly, significant (p < 0.001) increases in Hb levels were also observed in all studies. Multivariate linear regression analysis of the data for the Demetri et al. study indicated that both an Hb level increase and tumor response independently predicted QOL improvement. In all three studies, an increase in Hb level was found to correlate significantly with an improvement in QOL (Glaspy et al.: r = 0.27; p < 0.001; Demetri et al.: r = 0.235; p < 0.001; Gabrilove et al.: r = 0.173; p < 0.001). In the Demetri et al. study, assessments of changes in the FACT-An scale and the FACT-An Anemia subscale scores also showed significant (p < 0.001) improvements from baseline, with patients who achieved mean increases in Hb level 2 g/dl having the greatest increase in QOL as measured by these scales. Similarly, an assessment of changes in the FACT-An Anemia subscale score in the Gabrilove et al. study demonstrated a significant (p < 0.001) improvement from baseline. As in the Demetri et al. study, patients with Hb level increases 2 g/dl had the greatest improvements in QOL.

The findings of the three community-based studies were consistent with those of the Littlewood et al. [13] multinational, double-blind, placebo-controlled study of epoetin alfa mentioned earlier. In the Littlewood et al. study, QOL was assessed by means of the LASA, FACT-General (G) Total scale, FACT-An Fatigue subscale, and Medical Outcomes Study Short Form-36 (SF-36) Physical Component Summary and Mental Component Summary (primary measures), as well as by the FACT-An Anemia subscale (a secondary measure). The FACT-G Total scale, the FACT-An Fatigue subscale, and the three LASA scales are cancer-specific tools and have demonstrated sensitivities to Hb level; thus, these scales and subscales were designated as primary measures of the QOL effects of epoetin alfa. The two SF-36 scales, although also designated as primary measures, are not cancer specific, and were included as generic QOL instruments. Results of univariate analyses demonstrated significant differences favoring epoetin alfa over placebo for all five cancer-specific primary QOL scales (range: p = 0.0007 to p = 0.0048) and for the FACT-An Anemia subscale (p = 0.0007) (Fig. 5 and Fig. 6). Epoetin alfa was also favored over placebo for the SF-36 items, although the differences did not reach statistical significance. Consistent with the community-based studies, examination of the relationship between change in Hb level and change in QOL by correlation analysis revealed a strong and statistically significant (range: p = 0.0002 to p = 0.0325) correlation between these changes for all seven primary variables evaluated. Similarly, additional examination of the QOL data by multiple linear regression analysis, which controlled for disease progression and other possibly confounding variables, showed a significant advantage for epoetin alfa for the five primary cancer-specific QOL scales (range: p < 0.01 to p < 0.04), but not for the SF-36 scales (Fig. 5 and Fig. 6) [32]. Additionally, for the cancer-specific scales, significant correlations were demonstrated between baseline Hb level and QOL (r range: 0.14–0.26; all p < 0.05) and between change in Hb level and change in QOL (r range: 0.26–0.34; all p < 0.01). Overall, the results of these analyses provided convincing evidence that increasing the Hb level by administering epoetin alfa can significantly improve patient QOL.

View larger version (17K): [in this window] [in a new window]   Figure 5. Comparison of the mean change scores for the QOL LASA Energy Level, Ability to Do Daily Activities, Overall QOL items by treatment group. Shown are results of univariate and multivariate analyses. All p values, which correspond to primary measures, were adjusted for multiple comparisons (sequentially rejective Bonferroni procedure). Adapted with permission from Fallowfield et al. [32].

View larger version (15K): [in this window] [in a new window]   Figure 6. Comparison of the mean change scores for the QOL FACT-G Total scale and Fatigue subscale by treatment group. Shown are results of univariate and multivariate analyses. All p values, which correspond to primary measures, were adjusted for multiple comparisons (sequentially rejective Bonferroni procedure). Reprinted with permission from Fallowfield et al. [32].

Two additional studies, reported in 2003, have examined the clinical relevance of the observed effects of epoetin alfa on QOL. Experience with scales and other measures of QOL remains limited. Thus, the conduct of these studies was motivated largely by the perceived need to aid clinicians in interpreting the numerical changes in QOL parameters reported in clinical trials and thereby help them better manage anemia and its sequelae in patients undergoing chemotherapy.

In the first of these studies, Patrick et al. [35] analyzed the Hb and QOL data from the five cancer-specific QOL scales in the Littlewood et al. study [13] to establish minimally important differences (MIDs) in the scores that could be considered clinically meaningful. Patients (n = 375) were divided into two groups: namely, those who had experienced increases in Hb levels of 1 g/dl (improved) and those who had experienced Hb changes of <1 to –1 g/dl (stable). MIDs were established by calculating the difference in the mean change scores between the improved and stable patients for each QOL scale. Each MID value was then compared with the observed difference in the change score for the corresponding scale between the epoetin alfa- and placebo-treated patients. Differences between the treatment groups equal to or greater than the MID were considered clinically meaningful. As shown in Table 7, large, positive MIDs were found for all QOL scales, indicating that the differences in QOL scores between the epoetin alfa and placebo groups were clinically important.

	FURTHER PROFILING OF EPOETIN ALFA AND HB LEVELS

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
In addition to its impact on patient outcomes and QOL, other aspects of epoetin alfa therapy, such as dosage refinements aimed at improving therapeutic response, use in specific diagnostic categories of cancer, and outcomes unrelated to the hematopoietic effects of this agent are currently under evaluation. Chap et al. [37], in a prospective pilot study, evaluated the timeliness of response to epoetin alfa using a 60,000 IU once weekly loading dose in anemic patients with nonmyeloid malignancies receiving chemotherapy. (The usual starting dosages of epoetin alfa are 150 IU/kg or 10,000 IU three-times weekly or 40,000 IU once weekly.) Results of an interim analysis showed mean increases in Hb level of 1.1 g/dl by the fourth treatment week and of 2.6 g/dl by the eighth week, suggesting that once weekly administration of epoetin alfa (60,000 IU) rapidly and effectively increased Hb levels in the patient population studied. Hudis et al. [38] evaluated the effects of epoetin alfa in an open-label, nonrandomized, multicenter, community-based study in early-stage (Stage I–III) breast cancer patients [38]. The patients were undergoing 3–6 months of adjuvant chemotherapy consisting of an anthracycline with or without a taxane. Epoetin alfa therapy, which was continued for up to 24 weeks, was initiated with a starting dose of 40,000 IU once weekly. Results of an interim analysis based on 721 patients showed that epoetin alfa therapy maintained or improved Hb level (mean Hb level increase of 0.9 g/dl from baseline; p < 0.05) and QOL parameters during the course of adjuvant chemotherapy.

Patton et al. [39], in an open-label, nonrandomized pilot study, evaluated the efficacy of epoetin alfa at a dose of 60,000 IU once weekly followed by a maintenance dose of 120,000 IU every 3 weeks. Study participants were 20 anemic cancer patients with nonmyeloid malignancies who were undergoing chemotherapy. The initial dose (60,000 IU once weekly) was administered for 8 weeks. If, after week 8, Hb level increases by 2 g/dl above baseline, epoetin alfa maintenance therapy was administered for up to 24 weeks. The dosage was decreased by 20,000 IU if the Hb level increased to >15 g/dl or rose by >1.3 g/dl during any 2-week interval. Results of an interim analysis (mean treatment duration: 19.5 weeks) showed mean Hb changes from baseline of 1.0 g/dl by week 4, 2.7 g/dl by week 8, and 2.9 g/dl by the last measurement. In all, 13 patients received maintenance therapy. Thus, an epoetin alfa starting dose of 60,000 IU once weekly was effective at inducing an Hb increase of >2 g/dl between week 4 and week 8 of treatment, and this increase was maintained for the duration of the study, either with continued once weekly administration of 60,000 IU or administration of a three-times weekly maintenance dose of 120,000 IU.

In another dosing study, McKenzie et al. [40] retrospectively investigated the efficacy of epoetin alfa at increasing Hb levels when administered less than once weekly in a community-based setting. The study included 1,238 patients with a variety of malignancies, the most prevalent of which were breast cancer (22.1%) and lung cancer (18.7%). Response to epoetin alfa was defined as an Hb change from baseline of 1 g/dl without transfusion at week 4 or either an Hb change from baseline of 2 g/dl or an Hb level of 12 g/dl at weeks 8, 12, or 16 from the start of epoetin alfa therapy without transfusion within the previous 30 days. Among patients who received a starting dose of 40,000 IU, a mean dose of approximately 40,000 IU was administered in 95% or more of the subsequent visits, either once weekly (50.3% of patients), biweekly (32.4% of patients), or once every 3 weeks or more (17.3% of patients). Univariate analysis showed no significant differences in response rates among the three dosing groups at either week 4 or week 16. These findings suggest that, for selected patients, administration of epoetin alfa less frequently than once weekly (e.g., 40,000 IU biweekly or less often) is as effective as once weekly dosing at improving Hb levels. The investigators concluded that these findings supported the conduct of multivariate research to further examine the effect of extended epoetin alfa dosing schedules on Hb response and additional clinical trials to determine the effect of such schedules on patient outcomes.

Cancer patients, particularly those with breast cancer, often experience impaired cognition related to their chemotherapy, and this adverse effect may last for years after the end of therapy, impairing both the patient’s functional capacity and QOL. Studies by Brines et al. [41] and Cerami et al. [42] have demonstrated that epoetin alfa crosses the blood-brain barrier and exerts a neuroprotective effect on the central nervous system. This was evidenced by their findings in animal models that this agent reduced neural injury from ischemic stroke and blunt-force trauma, reduced the severity of experimental encephalomyelitis, and ameliorated the latency, severity, and mortality of kainate-induced seizures [41, 42]. These, and other encouraging findings [43], have led to trials of epoetin alfa aimed at improving cognitive function in patients undergoing chemotherapy. Data were presented by O’Shaughnessy et al. [44] at the 2002 San Antonio Breast Cancer Symposium (San Antonio, TX) suggesting that administration of epoetin alfa may have beneficial effects on cognitive function and QOL during and after chemotherapy. A larger, controlled trial to explore the potential benefits of epoetin alfa on cognitive function in chemotherapy patients has been initiated and is currently enrolling patients.

	POSTMEETING NOTES

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
Recent studies have evaluated patient outcomes when patients are treated to higher target Hb levels. It has been hypothesized that any beneficial effects of anemia treatment might be magnified with treatment to higher Hb levels. Three recent reports of double-blind trials were not available at the time of the workshop and are presented here for completeness. Two reports suggest an adverse impact on patient survival with rHuEPO when patients are treated to higher Hb levels, while the third reconfirms the good safety profile with no adverse impact on survival when epoetin alfa is used as indicated.

A randomized, multicenter, double-blind, placebo-controlled trial of epoetin alfa as an adjunct to chemotherapy in metastatic breast cancer patients without anemia was conducted in Europe, Canada, South Africa, and Australia to evaluate the effects of epoetin alfa on survival and was terminated early because of the observed higher mortality in the treatment group [45]. In that trial, patients with metastatic breast cancer, initially normal Hb levels (>13 g/dl), and receiving first-line chemotherapy were treated for up to 12 months with epoetin alfa to maintain their Hb levels in the normal range (>12 g/dl to <14 g/dl). The data showed a 12-month survival rate of 76% in the placebo group, versus 70% in the epoetin alfa group (p = 0.017) [45]. This difference was due primarily to a high mortality rate in the epoetin alfa group in the first 4 months of the study; subsequent follow-up beyond the treatment period showed convergence of the survival curves at 19 months.

The early deaths were primarily due to higher incidences of disease progression and thrombotic vascular events in the epoetin alfa group than in the placebo group. Since these results are in contrast to the numerous other studies in anemic cancer patients suggesting a survival benefit with epoetin alfa, extensive efforts were made to explain the unexpected findings, although no definitive conclusions could be made. Perhaps most importantly, the study was not designed to take into account an imbalance in risk factors between treatment groups other than the presence of metastases beyond bone involvement. A retrospective chart review of available data by independent investigators suggested that patients randomized to epoetin alfa were more likely to have adverse factors, such as advanced age, lower performance status, and greater extent of disease at study entry, and more risk factors for thrombotic vascular events [45]. Further, the study design did not assess or document important prognostic factors for survival, including definition of disease site, initial prognosis and specific assessment of tumor response at predefined intervals, and the type, duration, and dose of chemotherapy. Since the study was not adequately designed to account for these confounding variables, one cannot draw any definitive conclusions other than to use epoetin alfa only as it is indicated, that is, in cancer patients who become anemic during chemotherapy treatment.

In the second study, 351 anemic (Hb <12.0 g/dl, women; Hb <13.0 g/dl, men) patients receiving radiotherapy for treatment of head and neck cancer were randomized to receive epoetin beta at doses of 300 IU/kg three times weekly (n = 180) or placebo (n = 171) [16]. Patients were treated to achieve Hb levels higher that 14.0 g/dl in women and 15.0 g/dl in men. The primary end point was locoregional progression-free survival, which was found to be poorer in patients who received epoetin beta than in those who received placebo (adjusted relative risk: 1.62; 95% confidence interval: 1.22–2.14; p = 0.0008).

A very recently reported study demonstrated no adverse survival impact in women with high-risk breast cancer who received high-dose chemotherapy with or without epoetin alfa and in women who received conventional dose chemotherapy [46]. In that multicenter study (n = 1,284), women were randomized to receive a high-dose chemotherapy regimen of three cycles each of epirubicin (Ellence^®; Pharmacia and Upjohn; Portage, MI; 150 mg/m²), paclitaxel (Taxol^®; Bristol-Myers Squibb; 225 mg/m²), and cyclophosphamide (2,500 mg/m²) at 2-week intervals with G-CSF support (5 µg/kg/s.c. days 3–10) and further randomized to receive either epoetin alfa (150 IU/kg/s.c. three-times weekly) or no epoetin alfa. The comparison arm was conventional chemotherapy of four cycles of epirubicin/cyclophosphamide (90/600 mg/m²) followed by four cycles of paclitaxel (175 mg/m²) at 3-week intervals. Disease-free survival was significantly (p = 0.046) longer in patients who received the dose-dense chemotherapy regimen. Importantly, there was no difference in relapse-free survival between patients who received high-dose chemotherapy with epoetin alfa and those who received this treatment without epoetin alfa. The results of these trials are important in expanding our knowledge on the effects of rHuEPO and underscore the importance of continued study.

	SUMMARY

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 
The past decade has been characterized by a growing awareness of the role of anemia with respect to impairment of cancer patients’ physical well-being and QOL. However, appreciation of the significance of anemia in the oncology setting has recently been expanded by the results of clinical studies suggesting that anemia is also an important negative prognostic and predictive factor for several measures of patient outcome, including survival, in patients with a variety of solid tumors and hematologic malignancies. The results of other clinical studies have suggested that maintaining Hb levels in anemic cancer patients by means of epoetin alfa therapy may improve treatment outcomes, including overall survival, disease-free survival, and locoregional control, and additionally may improve patients’ QOL. These results must be tempered by the data from two randomized trials suggesting that maintaining normal Hb levels with erythropoietin during therapy could be associated with worse outcomes. Data from several studies have also shown that dosing schedules of epoetin alfa may be adjusted to maximize patient convenience. Clearly, addressing the problem of anemia is vital to the successful management of cancer patients with this complication, and additional rigorously designed and adequately powered trials are needed to determine the full potential of epoetin alfa with respect to improving survival and other treatment outcomes in anemic cancer patients.

	REFERENCES

Top Learning Objectives Abstract Introduction Hemoglobin as a Prognostic... Increased Hb and Treatment... Increased Hb Level and... Further Profiling of Epoetin... Postmeeting Notes Summary References

 

1. Caro JJ, Salas M, Ward A et al. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 2001;91:2214–2221.[CrossRef][Medline]
2. Littlewood TJ. The impact of hemoglobin levels on treatment outcomes in patients with cancer. Semin Oncol 2001;28(suppl 8):49–53.
3. Harrison LB, Chadha M, Hill RJ et al. Impact of tumor hypoxia and anemia on radiation therapy outcomes. The Oncologist 2002;7:492–508.[Abstract/Free Full Text]
4. Van Belle SJ, Cocquyt V. Impact of haemoglobin levels on the outcome of cancers treated with chemotherapy. Crit Rev Oncol Hematol 2003;47:1–11.[Medline]
5. Henke M, Sindlinger F, Ikenberg H et al. Blood hemoglobin level and treatment outcome of early breast cancer. Strahlenther Onkol 2004;180:45–51.[CrossRef][Medline]
6. Muenstedt K. Hemoglobin concentration before chemotherapy is an independent prognostic factor in ovarian carcinomas. Proc Am Soc Clin Oncol 2002;21:216a.
7. Sevelda P, Gnant M, Lainz K. Influence of anemia on local relapse-free survival (LRFS) of premenopausal primary breast cancer patients under adjuvant CMF chemotherapy: an analysis of the Austrian Breast Cancer Study Group. Proc Am Soc Clin Oncol 2002;21:65a.
8. Morganti AG, Forni F, Macchia G et al. Chemoradiation of unresectable pancreatic carcinoma: impact of pretreatment hemoglobin level on patterns of failure. Strahlenther Onkol 2003;179:87–92.[CrossRef][Medline]
9. Grogan M, Thomas GM, Melamed I et al. The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 1999;86:1528–1536.[CrossRef][Medline]
10. Thomas G. The effect of hemoglobin level on radiotherapy outcomes: the Canadian experience. Semin Oncol 2001;28(suppl 8):60–65.
11. Antonadou D, Cardamakis E, Puglisi M et al. Erythropoietin enhances radiation treatment efficacy in patients with pelvic malignancies. Final results of a randomized phase III study. Eur J Cancer 2001;37(suppl 6):S144.
12. Glaser CM, Millesi W, Kornek GV et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001;50:705–715.[CrossRef][Medline]
13. 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;19:2865–2874.[Abstract/Free Full Text]
14. Blohmer JU, von Minckwitz G, Paepke S et al. Sequential adjuvant chemo-radiotherapy with vs. without erythropoietin for patients with high-risk cervical cancer—second analysis of a prospective, randomized, open and controlled AGO- and NOGGO-intergroup study. Proc Am Soc Clin Oncol 2002;21:206a.
15. Pangalis GA, Siakantaris MP, Angelopoulou MK et al. Downstaging Rai stage III B-chronic lymphocytic leukemia patients with the administration of recombinant human erythropoietin. Haematologica 2002;87:500–506.[Abstract/Free Full Text]
16. Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362:1255–1260.[CrossRef][Medline]
17. Littlewood T, Bajetta E, Rapoport B et al. Early administration of epoetin alfa optimizes anemia management with respect to hematologic and quality of life (QOL) outcomes in anemic cancer patients (pts) undergoing chemotherapy. Blood 2002;100:18b.
18. Cella D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 1997;34(suppl 2):13–19.[Medline]
19. Langer C, Barsevick A, Bruner D et al. Correlation of quality of life (QOL) with survival, treatment response, and anemia in patients with advanced non-small cell lung cancer (NSCLC) treated with carboplatin and paclitaxel. Lung Cancer 1997;18(suppl 1):23.
20. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91:1616–1634.[Abstract/Free Full Text]
21. Crawford J, Cella D, Cleeland CS et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 2002;95:888–895.[CrossRef][Medline]
22. Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin level for optimal quality of life: results of an incremental analysis. Proc Am Soc Clin Oncol 1999;18:574a.
23. 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;15:1218–1234.[Abstract/Free Full Text]
24. 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;16:3412–3425.[Abstract]
25. Ludwig H, Fritz E, Kotzmann H et al. Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 1990;322:1693–1699.[Abstract]
26. Abels RI. Recombinant human erythropoietin in the treatment of the anaemia of cancer. Acta Haematol 1992;87(suppl 1):4–11.
27. 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;19:2875–2882.[Abstract/Free Full Text]
28. Soignet S. Management of cancer-related anemia: epoetin alfa and quality of life. Semin Hematol 2000;37(suppl 6):9–13.[Medline]
29. Demetri GD, Gabrilove JL, Blasi MV et al. Benefits of epoetin alfa in anemic breast cancer patients receiving chemotherapy. Clin Breast Cancer 2002;3:45–51.
30. Curt GA. The impact of fatigue on patients with cancer: overview of FATIGUE 1 and 2. The Oncologist 2000;5(suppl 2):9–12.[Abstract/Free Full Text]
31. Curt GA, Breitbart W, Cella D et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. The Oncologist 2000;5:353–360.[Abstract/Free Full Text]
32. Fallowfield L, Gagnon D, Zagari M et al. Multivariate regression analyses of data from a randomised, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. Br J Cancer 2002;87:1341–1353.[CrossRef][Medline]
33. Shasha D, George M, Harrison L. Significant relationships between hemoglobin (Hb) levels and quality of life (QoL) during chemoradiation: findings from an incremental analysis of a 442-patient, prospective, community-based epoetin alfa study. Int J Radiat Oncol Biol Phys 2002;54(suppl 2):48.[CrossRef]
34. Shasha D, George M, Harrison L. Once-weekly dosing of epoetin alfa increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Blood 2000;96:434a.
35. Patrick DL, Gagnon DD, Zagari MJ et al. Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa. Eur J Cancer 2003;39:335–345.
36. Cella D, Zagari MJ, Vandoros C et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 2003;21:366–373.[Abstract/Free Full Text]
37. Chap L, George M, Glaspy J. Evaluation of epoetin alfa (Procrit) 60,000 U once weekly in anemic cancer patients receiving chemotherapy. Proc Am Soc Clin Oncol 2002;21:264b.
38. Hudis C, Williams D, Gralow J. Epoetin alfa maintains hemoglobin levels and quality of life in breast cancer patients during adjuvant chemotherapy. Proc Am Soc Clin Oncol 2002;21:380a.
39. Patton J, Camp M, Kuzur M et al. Epoetin alfa 60,000 U once weekly followed by 120,000 U every 3 weeks maintains hemoglobin levels in anemic cancer patients undergoing chemotherapy. Blood 2002;100:16b.
40. McKenzie S, Heifetz L, Duh M et al. Effectiveness of epoetin alfa beyond once-weekly dosing schedules in the oncology community practice setting. Blood 2002;100:501b.
41. Brines ML, Ghezzi P, Keenan S et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000;97:10526–10531.[Abstract/Free Full Text]
42. Cerami A, Brines ML, Ghezzi P et al. Effects of epoetin alfa on the central nervous system. Semin Oncol 2001;28(suppl 8):66–70.[Medline]
43. Farrell F, Lee A. The erythropoietin receptor and its expression in tumor cells and other tissues. The Oncologist 2004;9(suppl 5):18–30.[Abstract/Free Full Text]
44. O’Shaughnessy J, Vukelja S, Savin M et al. Impact of epoetin alfa on cognitive function, asthenia, and quality of life in women with breast cancer receiving adjuvant or neoadjuvant chemotherapy: analysis of 6-month follow-up data. Breast Cancer Res Treat 2002;76:S138.
45. Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly. BEST Investigators and Study Group. Lancet Oncol 2003;4:459–460.[CrossRef][Medline]
46. Möbus VJ, Untch M, Du Bois A et al. Dose-dense sequential chemotherapy with epirubicin (E), paclitaxel (T) and cyclophosphamide (C) (ETC) is superior to conventional dosed chemotherapy in high-risk breast cancer patients (4 +LN). First results of an AGO-trial. Proc Am Soc Clin Oncol 2004;22:543a.
47. Albain KS, Crowley JJ, LeBlanc M et al. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991;9:1618–1626.[Abstract]
48. Ohlhauser C, Bulzebruck H, Ebert W et al. Prognostic factors for survival in inoperable non-small-cell lung cancer: a multivariate regression analysis of 456 patients with radiation therapy. Onkologie 1997;20:126–131.
49. Wilhelm R, Kovacs G, Heinrichsohn D et al. [Survival of exclusively irradiated patients with NSCLC. Significance of pretherapeutic hemoglobin level.] Strahlenther Onkol 1998;174:128–132. German.[Medline]
50. Ylisirnio S, Sassi ML, Risteli J et al. Serum type I collagen degradation markers, ICTP and CrossLaps, are factors for poor survival in lung cancer. Anticancer Res 1999;19:5577–5581.[Medline]
51. Eisenhauer EA, Vermorken JB, van Glabbeke M. Predictors of response to subsequent chemotherapy in platinum pretreated ovarian cancer: a multivariate analysis of 704 patients. Ann Oncol 1997;8:963–968.[Abstract/Free Full Text]
52. Obermair A, Petru E, Windbichler G et al. Significance of pretreatment serum hemoglobin and survival in epithelial ovarian cancer. Oncol Rep 2000;7:639–644.[Medline]
53. Obermair A, Cheuk R, Horwood K et al. Impact of hemoglobin levels before and during concurrent chemoradiotherapy on the response of treatment in patients with cervical carcinoma: preliminary results. Cancer 2001;92:903–908.[CrossRef][Medline]
54. Marinaccio M, Mele E, DeMarino E et al. Pretreatment serum hemoglobin as a prognostic factor in epithelial ovarian cancer. Proc Am Soc Clin Oncol 2002;21:216a.
55. Masuda H, Kurita Y, Fukuta K et al. Significant prognostic factors for 5-year survival after curative resection of renal cell carcinoma. Int J Urol 1998;5:418–422.[Medline]
56. Motzer RJ, Mazumdar M, Bacik J et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17:2530–2540.[Abstract/Free Full Text]
57. Sengelov L, Kamby C, Geertsen P et al. Predictive factors of response to cisplatin-based chemotherapy and the relation of response to survival in patients with metastatic urothelial cancer. Cancer Chemother Pharmacol 2000;46:357–364.[CrossRef][Medline]
58. Vollmer RT, Kantoff PW, Dawson NA et al. A prognostic score for hormone-refractory prostate cancer: analysis of two cancer and leukemia group B studies. Clin Cancer Res 1999;5:831–837.[Abstract/Free Full Text]
59. Wagner W, Hermann R, Hartlapp J et al. Prognostic value of hemoglobin concentrations in patients with advanced head and neck cancer treated with combined radio-chemotherapy and surgery. Strahlenther Onkol 2000;176:73–80.[CrossRef][Medline]
60. Moullet I, Salles G, Ketterer N et al. Frequency and significance of anemia in non-Hodgkin’s lymphoma patients. Ann Oncol 1998;9:1109–1115.[Abstract/Free Full Text]
61. Federico M, Vitolo U, Zinzani PL et al. Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi. Blood 2000;95:783–789.[Abstract/Free Full Text]
62. Callea V, Clo V, Morabito F et al. Retrospective analysis of mantle cell lymphoma: experience of the "Gruppo Italiano per lo Studio dei Linfomi" (GISL). Haematologica 1998;83:993–997.[Abstract/Free Full Text]
63. Samaha H, Dumontet C, Ketterer N et al. Mantle cell lymphoma: a retrospective study of 121 cases. Leukemia 1998;12:1281–1287.[CrossRef][Medline]
64. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 1998;339:1506–1514.[Abstract/Free Full Text]
65. Landman-Parker J, Pacquement H, Leblanc T et al. Localized childhood Hodgkin’s disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy—results of the French Society of Pediatric Oncology Study MDH90. J Clin Oncol 2000;18:1500–1507.[Abstract/Free Full Text]
66. Liao Z, Ha CS, Fuller LM et al. Subdiaphragmatic stage I & II Hodgkin’s disease: long-term follow-up and prognostic factors. Int J Radiat Oncol Biol Phys 1998;41:1047–1056.[CrossRef][Medline]
67. Keating MJ, Smith TL, Lerner S et al. Prediction of prognosis following fludarabine used as secondary therapy for chronic lymphocytic leukemia. Leuk Lymphoma 2000;37:71–85.[Medline]
68. Kern W, Schoch C, Haferlach T et al. Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance of cytogenetic abnormalities. Leukemia 2000;14:226–231.[CrossRef][Medline]
69. Morel P, Monconduit M, Jacomy D et al. Prognostic factors in Waldenström macroglobulinemia: a report on 232 patients with the description of a new scoring system and its validation on 253 other patients. Blood 2000;96:852–858.[Abstract/Free Full Text]

This article has been cited by other articles:

				C. A. Hudis and S. Van Belle Introduction: Examining the Potential Impact of Anemia Treatment on Clinical Outcomes in Anemic Cancer Patients Oncologist, November 1, 2004; 9(suppl_5): 1 - 3. [Full Text] [PDF]

				K. Blackwell, P. Gascon, G. Sigounas, and L. Jolliffe rHuEPO and Improved Treatment Outcomes: Potential Modes of Action Oncologist, November 1, 2004; 9(suppl_5): 41 - 47. [Abstract] [Full Text] [PDF]

				H. Ludwig, C. A. Hudis, G. Goss, and B. Leyland-Jones Epoetin Alfa: Future Directions and Future Research Oncologist, November 1, 2004; 9(suppl_5): 70 - 73. [Full Text] [PDF]

This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hudis, C. A. Articles by Muenstedt, K. Search for Related Content PubMed PubMed Citation Articles by Hudis, C. A. Articles by Muenstedt, K.