At the 2007, 20th Anniversary International MASCC/ISOO Symposium, neutropenia, thrombocytopenia, and anemia remained active areas of discussion, with a focus on individualizing care for patients. Side effects associated with erythropoietin stimulating agents (ESAs), specifically thrombosis, have brought forward the issue that supportive care may carry its own risks, and these risks must be weighed against overall benefits. In addition, supportive care in the pediatric oncology population was recognized at the 2007 MASCC symposium as an area where additional studies are warranted.


Pegfilgrastim Versus Filgrastim

Dr. Gary Lyman, along with other researchers from the University of Rochester and Cerner, Inc., conducted a meta-analysis of randomized controlled trials to compare pegfilgrastim to filgrastim for specified endpoints. PubMed and EMBASE were searched for randomized controlled trials comparing pegfilgrastim to filgrastim utilizing only approved doses for both agents among patients with lymphoid malignancies or solid tumors being treated with myelosuppressive therapy between 1990 and 2006. Researchers pooled data including rates of grade IV neutropenia, rates of febrile neutropenia (FN), time to absolute neutrophil count (ANC) recovery and bone pain.[[1]]( "_ednref1")

  • Five randomized controlled trials meeting established criteria for the meta-analysis were identified.
  • Only one clinical trial demonstrated a significant reduction in FN with pegfilgrastim compared to filgrastim, with a relative reduction of 50% (p=0.027).
  • Pooled data, however, indicated a significant reduction in FN with the use of pegfilgrastim over filgrastim (RR=0.64).
  • Grade IV neutropenia rates, time to ANC recovery and bone pain incidence were similar between both agents in the pooled analysis.

Pegfilgrastim has been well established as a reasonable alternative to filgrastim, with equal if not superior efficacy and the benefits provided by the significant reduction in dosing frequency. Research continues in the direction of identifying patients who are at a high risk of developing neutropenia and will therefore benefit from prophylactic measures utilizing growth factors or who are optimal candidates for early intervention.

Risk Assessment Models

Researchers from the ANC Study Group conducted a prospective study to develop risk models for severe or febrile neutropenia (together classified as neutropenia complications (NC)) among patients with non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) undergoing chemotherapy.[[2]]( "_ednref2") The study included 893 patients with data on one or more cycles of chemotherapy (n=665 [NSCLC], n=198 [SCLC]). Patients had not received prior chemotherapy and were treated at one of 115 randomly selected oncology sites within the U.S.

Independent risk factors for NC in patients with NSCLC included the following:

  • Hyperglycemia (HR=1.8),
  • Elevated bilirubin (HR=2.6),
  • Elevated alkaline phosphatase (HR1.7),
  • Recent surgery (HR1.8),
  • Chemotherapy regimens incorporating cisplatin or carboplatin (HR=4.9); docetaxel (HR=2.2); gemcitabine (HR=2.8); vinorelbine (HR=5.1), and/or
  • Planned relative dose intensity > 85% (HR=1.8).

Independent risk factors for NC in patients with SCLC included the following:

  • Elevated bilirubin (HR=3.9),
  • Concurrent immunosuppressives (HR=2.0),
  • Topoisomerase inhibitor-based regimens (HR=5.1),
  • Age greater than 65 years (HR=1.9), and/or
  • Thrombocytopenia (HR=3.4).

Growth factor prophylaxis reduced NC risk by approximately 60% in both groups of patients. The researchers concluded that “multivariate analysis for NC identifies overlapping as well as distinct risk factors for patients with NSCLC and SCLC receiving systemic chemotherapy. Such risk models may have applicability in identifying patients at increased risk for early NC. Independent validation of these models will be conducted in a separate population of lung cancer patients.”

Pediatric Risk Assessment Models

As research is moving in the direction of establishing risk assessment models for neutropenia in adults with cancer, there is more limited data involving children undergoing treatment for cancer. As FN is a life-threatening emergency in children, the establishment of algorithms for these patients who would benefit the most from prophylaxis against neutropenia would be of benefit, as they have been with adults.

Researchers from Switzerland conducted a retrospective study to identify potential variables that are associated with risk of neutropenia among children with cancer undergoing chemotherapy with the intent of identifying high-risk patients.[[3]]( "_ednref3") This study was a single-site cohort study with data collection from chart review. Children up to 17 years of age who were diagnosed between 1993 and 2004 were included (n=360). Median age at diagnosis was 5.8 years. Chemotherapy intensity was graded on four levels, with one being the least intense and four being myeloablative therapy.

Identified significant and independent predictors of FN included the following:

  • Intensity of chemotherapy (myeloablative therapy was associated with the greatest rate of FN [RR=5.88; p<0.001]),
  • Presence of central venous catheter,
  • Known past FN, and/or
  • Two or more siblings.

A longer time since diagnosis and complete remission were both associated with a decreased risk of FN. Identified significant and independent predictors of FN with bacteremia were the same as for FN with the exception of the number of siblings (level two intensity of chemotherapy also did not reach significance in its correlation to risk of FN with bacteremia). Patients diagnosed with cancer between the ages of 4 and 8 had significantly reduced risk of FN with bacteremia.

The researchers stated that “besides the strong influence of chemotherapy intensity, factors related to patients, management, and course of disease were important predictors of FN in total and FN with bacteremia.”

Another study conducted by researchers in Switzerland was conducted to evaluate mannose-binding lectin-associated serine protease-2 (MASP-2) deficiency and its potential impact on risk of infection among pediatric cancer patients undergoing chemotherapy.[[4]]( "_ednref4") MASP-2 is an integral component of complement activation through the leptin pathway. A relatively common genetic polymorphism is MASP-2 deficiency; however, its effects on risk of infection are unknown. This study included 94 children who were tested through ELISA for MASP-2 deficiency at the time of diagnosis, 10% of whom had the MASP-2 deficiency.

  • Patients with the MASP-2 deficiency had over a two-fold greater risk of developing FN (p=0.002).
  • The increased risk of FN resulted in significantly prolonged cumulative duration of hospital stay and significantly more intravenous antimicrobial therapy.

The researchers stated that “MASP-2 deficiency represents a novel risk factor for chemotherapy-related infections.” Taken together, results from these studies can help to build the foundation necessary for ultimately establishing an accurate risk assessment model for pediatric patients with cancer who are to undergo therapy.

Sepsis Burden

In line with preventing or reducing neutropenia through risk assessment models, researchers from Germany conducted a study to help quantify the burden of sepsis occurrence among patients treated with myelosuppressive therapy.[[5]]( "_ednref5") This prospective observational, longitudinal study included 180 patients with NSCLC or lymphoma who underwent a total of 633 chemotherapy cycles. Overall, seven patients (3.9%) experienced an episode of sepsis.

  • 102 units of blood components were used for blood transfusion.
  • The mean length of stay in the ICU was almost 20 days.
  • Treatment cost per episode varied, but was up to 68,000 euros.

This data serves as a reminder of the burden of neutropenia in addition to its life-threatening effects, and the importance of its prevention.

Prophylactic Management of Neutropenia: Colorectal Cancer

The recent emergence of new chemotherapy agents for the treatment of colorectal cancer has provided greater treatment options for these patients. Newer chemotherapy agents now available for colorectal cancer include oxaliplatin and irinotecan in combination with 5-fluorouracil. Administration of regimens that include these agents every two weeks (Q2W) decreases the rate of gastrointestinal symptoms; however, the risk of neutropenia becomes a common toxicity.

Researchers from Loma Linda University, the University of California at Los Angeles, Cancer and Blood Specialists of Nevada and the Comprehensive Blood and Cancer Center in California conducted a clinical trial to evaluate the effectiveness of pegfilgrastim as prophylaxis against neutropenia for patients with colorectal cancer being treated with Q2W FOIL (5FU, oxaliplatin, irinotecan), FOLFOX (5FU, oxaliplatin), or FOLFIRI (5FU, irinotecan). This Phase II, randomized, placebo controlled trial included 214 patients with locally advanced or metastatic colorectal cancer who were randomized to pegfilgrastim or placebo.[[6]]( "_ednref6")

  • Grades 3-4 neutropenia occurred in 13% of patients who received pegfilgrastim, compared with 43% of patients who received placebo (OR= 0.19; p<0.0001).
  • FN occurred in 2% of patients treated with pegfilgrastim and 8% of patients who received placebo.
  • Pegfilgrastim was well tolerated.

These results provide more data indicating that prophylaxis with pegfilgrastim in colorectal cancer patients treated with Q2W therapy including irinotecan and/or oxaliplatin appears to protect against neutropenia. The overall risk of FN is below that recommended by current NCCN/ASCO guidelines for routine first cycle prophylaxis. The development of risk assessment models in this population will be particularly useful in the targeted use of myeloid growth factors.


Effective treatment of chemotherapy-induced thrombocytopenia among cancer patients is important due to the potential of hemorrhagic complications, including death. Currently, oprelvekin or transfusions may be used to treat chemotherapy-induced thrombocytopenia, however, both strategies come with risks and potential diminished responses. The future direction of treatment for chemotherapy-induced thrombocytopenia includes the use of thrombopoietins (TPO), such as recombinant thrombopoietins, TPO peptide mimetics and thrombopoietic fusion proteins, and platelet growth factors.

TOP Mimetics

The second generation of TPO-like agents has been developed by identifying peptides that bind to the TPO receptor with high affinity. Because they bear limited structural resemblance to TPO, but still bind and activate the TPO receptor, these compounds are called TPO mimetics. Several peptides have been identified, and they have been further modified to both prolong their half-life in plasma as well as to increase their efficiency in activating the TPO receptor. The theoretical advantage of these compounds over standard recombinant TPO is that they bear little structural similarity with native TPO, and should not trigger auto-immune, anti-TPO antibodies like PEG-MDGF.

AMG 531 is one of the first pharmaceuticals in the peptide TPO mimetic category. It is composed of several copies of the TPO receptor-binding peptide spliced into a recombinant antibody. This peptide mimetic competes with TPO for binding to the TPO receptor, and activates the receptor in an identical fashion to endogenous TPO. When administered subcutaneously to humans, AMG 531 produces a dose-dependent increase in platelet counts.

Dr. Hagop Kantarjian and colleagues conducted a multi-institutional Phase I/ II study to evaluate the safety and efficacy of AMG 531 for the treatment of thrombocytopenia among patients with myelodysplastic syndromes (MDS). Preliminary results were presented at the 2007 MASCC meeting. This study has enrolled 28 subjects to date; 9 of whom are transfusion-dependent.[[7]]( "_ednref7")

  • 61% of patients achieved a platelet response.
  • Of the 18 patients who have completed at least 12 weeks of treatment, nearly half have achieved a durable response lasting at least eight consecutive weeks.
  • Two patients experienced dose-limiting toxicities (DLTs), both due to high platelet levels.
  • During the four-week treatment, the median baseline platelet count among responders was 25×109/L and the median peak platelet count among responders was 130×109/L.

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AMG 531 has also been evaluated in patients with immune thrombocytopenic purpura (ITP). Researchers from the University of Oklahoma and the New York-Presbyterian hospital conducted an analysis of health-related quality of life (HRQOL) among patients with ITP who were treated with AMG 531.[[8]]( "_ednref8") This analysis included 36 patients who completed the ITP Patient Assessment Questionnaire (ITP-PAQ) which has specific quality of life related scales including the following:

  • Physical Health (PH)- symptoms, fatigue, bother, and activity;
  • Emotional Health (EH) – psychological and fear;
  • Quality of life (QOL) – overall, social and work; and
  • Women’s reproductive health.
  • Each of these scales is scored from 0 (worst) to 100 (best). Patients completed the questionnaires one week prior to AMG 531 and at week 24.
  • PH realms were increased between 7.4 and 9.4 units (p<0.05).
  • QOL –work was increased 7.9 units (p=0.014).

Importantly, patients who achieved a doubling of platelet count above baseline for at least six consecutive weeks in the absence of rescue medication demonstrated greater improvement in all endpoints of the scales.

Prevalence and Resource Utilization

Hemorrhagic complications are often caused by thrombocytopenia or platelet dysfunction in myelodysplastic syndromes (MDS). However, little is known about the incidence and clinical impact in this patient population. Thus, researchers from MD Anderson Cancer Center, H. Lee Moffitt Cancer Center and Research Institute, Cancer Care Centers of South Texas/US Oncology and the Cleveland Clinic Taussig Cancer Center conducted a data review to help answer this question. The researchers conducted a retrospective chart review of all patients who were admitted to the MD Anderson Cancer Center since 1980 and a literature search including Medline, EMBASE and Cochrane databases.[[9]]( "_ednref9")

  • Overall, 40%-65% of patients diagnosed with MDS also had thrombocytopenia.
  • Prior to therapy for MDS, thrombocytopenia frequency was 65%.
  • MDS treatment-related thrombocytopenia occurred in 50% of patients who were treated with lenalidomide, azacitidine, or a combination of idarubicin, cytarabine and topotecan.
  • There was wide variability in hemorraghic complications: 3%-53%.
  • Hemorrhagic death occurred in 14%-24% of patients.

These results underscore the importance of preventing or reducing thrombocytopenia in patients with cancer. In addition to the prevalence of thrombocytopenia, resource utilization is of importance to further understand the impact of this condition.

Researchers from the MD Anderson Cancer Center in Houston, Texas recently conducted a study to evaluate medical resource use for managing thrombocytopenia in patients with cancer.[[10]]( "_ednref10") This study included the evaluation of a health plan claims database from 2000-2004 that involved 6,378 patients with 11,298 chemotherapy episodes.

  • 62.2% of all chemotherapy episodes included thrombocytopenia, platelet transfusion and/or hemorrhage. Of those, 30.5% included platelet transfusions, and53.6% included evidence of hemorrhage.
  • The average number of office visits per cycle for patients with thrombocytopenia increased by 31% compared to control cycles without evidence of thrombocytopenia, transfusion, or hemorrhage.
  • Length of stay in a medical facility was increased from an average of one day to nearly 10 days for patients diagnosed with thrombocytopenia requiring transfusions.

The researchers concluded that “prevention of thrombocytopenia and hemorrhage should substantively reduce medical resource use, including reduction in demand on the blood supply.”


Due to its insidious symptoms, anemia in the cancer chemotherapy patient has often been under-recognized and under-treated. Furthermore, the recent concerns surrounding erythropoietin stimulating agents (ESAs) used outside standard indications may discourage its appropriate use in patients who could derive benefit from them, as physicians may become more hesitant to prescribe ESAs. However, anemia and its sequelae contribute significantly to a decreased quality of life for patients, as well as reductions in optimal therapy and increased resource utilization of transfusion.

Risks and Benefits of ESAs

In light of recent concerns over ESAs, researchers from Columbia University, the NY Lung Cancer Alliance and the Regina Elena National Cancer Institute in Rome conducted a review to further evaluate the risks and benefits of ESAs in cancer patients.[[11]]( "_ednref11") This review included randomized trials comparing ESAs in addition to chemotherapy compared with placebo and chemotherapy. Trials were from Medline, abstracts from congresses and regulatory documents. Fifteen studies including nearly 4,000 patients met the criteria for the review.

  • Thrombotic events were increased in the ESA arms in 13 of 15 studies.
  • Thrombotic events were particularly increased in trials of lenalidomide plus an ESA or thalidomide plus an ESA.

The researchers concluded that “the benefits of ESA (raising Hb levels without QL increase) versus the risks (significantly increased thrombosis) require close scrutiny and new guidelines need to be determined for their continued use.” Further studies evaluating which agents may be associated with greater risks of thrombosis when used with ESAs, as well as understanding patient-specific risk factors for thrombosis may help to individualize therapy.

ESA Guideline Compliance

Researchers from United BioSource Corporation and Pacific Hematology/Oncology Associates in California reviewed electronic medical records to understand compliance rates with guidelines for ESAs in chemotherapy induced anemia (CIA).[[12]]( "_ednref12") The researchers reviewed the Varian Medical oncology database of electronic medical records from 17 oncology practices in the United States, which included over 13,000 cancer patients from 2004 to 2006. Rates of compliance with ESAs were referenced against the American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO) guidelines and the National Comprehensive Cancer Network (NCCN) guidelines. The ASH/ASCO guidelines recommend initiating ESAs for CIA if hemoglobin (Hb) levels are 10 or less g/dL and the NCCN guidelines recommend ESA initiation if Hb levels are less than 11 g/dL.

  • During Cycle 1, 49.1% of patients received ESAs at hemoglobin levels < 11 g/dL.
  • Only approximately 3%-4% of patients received ESAs at hemoglobin levels >12 g/dL, while 20.4% received ESAs at hemoglobin levels between 11-12 g/dL.
  • Hemoglobin level data was missing in 23.8% of the reviewed records.
  • The use of ESAs changed little from 2004 to 2006.
  • CIA in the Pediatric Population

Chemotherapy-induced anemia also has significant impact on pediatric cancer patients. Researchers from Romania conducted a study to evaluate ESAs in pediatric cancer patients with anemia.[[13]]( "_ednref13") This trial included 42 patients who were 19 years of age or younger diagnosed with solid tumors or hematologic malignancies. Hemoglobin levels were >8 g/dL and patients received epoetin beta during treatment for cancer and two months following completion of therapy.

  • After 12 weeks, 78% of patients achieved hemoglobin levels between 11-13 g/dL.
  • Responses in hemoglobin levels were maintained throughout treatment in 80% of responders.
  • Among patients who responded to ESA therapy with an increase in hemoglobin level > 2 g/dL, improvement in quality of life was significantly better compared with patients who did not respond.

The researchers concluded that significant improvements in quality of life were achieved for pediatric cancer patients with CIA who responded to ESA therapy. Longer follow-up is necessary to determine if any long-term outcomes may have been affected with ESA treatment.

With the change in CMS policy to only allow ESA use for hemoglobin values <10 g/dL, these usage patterns are likely to change in the next year, pending continued discussions between the FDA, CMS and guidelines issued by ASH, ASCO and the NCCN.


Results from the 2007 MASCC Symposium regarding myelosuppression indicate that the identification of risk factors that stratify patients in either a high risk or low risk category for developing myelosuppression is an active area of research. Identification of these risk factors will aid in the implementation of risk assessment models which will further individualize care. Similarly, understanding the risks and consequences of hematopoietic growth factors, such as ESAs, as well as the alternative strategy of transfusion, is vital in optimizing supportive care.

Safely reducing the risk of myelosuppression for patients with cancer undergoing myelosuppressive therapy allows for optimal dosing of therapy, improved quality of life and ultimately improved outcomes of cancer treatment. Research will undoubtedly continue to individualize therapy through a reduction in side effects, particularly myelosuppression. New agents are on the horizon for thrombocytopenia and guidelines are an area of active discussion in the use of ESAs for improving hemoglobin levels. Longer follow-up, pooled analyses and prospective trials of specific treatment regimens are all potentially valuable strategies in providing insight to the safest way in which to reduce or prevent myelosuppression in patients undergoing treatment for cancer.


[[1]]( "_edn1") Lyman G, Pinto L, Doan Q, et al. Comparison of Pegfilgrastim with Filgrastim on Febrile Neutropenia, Grade IV neutropenia and Bone Pain: Meta-Analysis of Randomized Controlled Trials. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-166.

[[2]]( "_edn2") Crawford J, Dale D, Kuderer N, et al. Risk Model for Neutropenic Complications in Lung Cancer Patients Receiving Cancer Chemotherapy. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-170

[[3]]( "_edn3") Wicki S, Keisker A, Hirt A, et al. Predicting Fever and Neutropenia in Children with cancer. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-173

[[4]]( "_edn4") Schlapbach L, Aebi C, Otth M, et al. Deficiency of Mannose-Binding Lectin-Associated Serine Protease-2 (MASP-2) is Associated with an Increased risk of chemotherapy-Related Infections in Pediatric Cancer Patients. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-175.

[[5]]( "_edn5") Paessens B, Berger K, Ihbe-Heffinger A, et al. Sepsis after Myelosuppressive Chemotherapy in NSCLC and Lymphoma Patients: Resource Use and Direct Costs from the Perspective of a German University Hospital. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-210

[[6]]( "_edn6") Malik I, Gollard R, Patel R, et al. Pegfilgrastim Reduces the Incidence of Neutropenia in Patients with Locally Advanced or Metastatic Colon Cancer Receiving Chemotherapy Administered Every 2 Weeks as First- or Second-Line Treatment : a Phase 2, Double-Blind, Placebo-Controlled Study. Abstract #P-167.

[[7]]( "_edn7") Kantarjian H, Giles F, Fenaux P, et al. Evaluating Safety and Efficacy of AMG 531 for the Treatment of Thrombocytopenic Patients with Myelodysplastic Syndrome (MDS): Preliminary Results of Phase 1/ 2 Study. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-150.

[[8]]( "_edn8") George J, Bussel J, McMillan R, et la. Analysis of Health-Related Qualtiy of Life in Patients Receiving AMG 531 Using the Disease-Specific Immune Thrombocytopenic Purpura Patients Assessment Questionnaire. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-149.

[[9]]( "_edn9") Kantarjian H, Giles F, List A, et al. Thrombocytopenia in MDS: Incidence and Impact. P-148.

[[10]]( "_edn10") Grotzinger K, Baranwal A, Vadhan-Raj S. Resource Utilization in Cancer Paitents with Thrombocytopenia and/or Hemorrhage. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-211.

[[11]]( "_edn11") Raftopoulos H, Gralla R, Bria E. Using Erythroid Stimulating Agents (ESA) in Cancer Patients: a Balance of Risks and Benefits Based on a Comprehensive Review of Randomized Studies Including 3,935 Patients Emphasizing Trials with Tumor Response and Survival Endpoints. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-160.

[[12]]( "_edn12") Luo W, Nordstrom B, Ranganathan G, et al. Adherence to Guidelines for use of Erythropoiesis Stimulating Proteins with Chemotherapy Induced Anemia: Trends from Electronic Medical Records. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-161.

[[13]]( "_edn13") Dragomir M, Milcu R, Radu C, et al. Epoetin Beta for the Treatment of Anemia in Children with Cancer. Proceedings from the 20th Anniversary International MASCC/ISOO Symposium, St. Gallen, Switzerland, June 27 – 30, 2007. Abstract #P-165.

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