Optimization of Oncology Supportive Care through Innovative Biotechnology

At an industry-sponsored symposium held October 20, 2002, in conjunction with the American College of Clinical Pharmacy’s Annual Meeting, three speakers addressed recent advances in the treatment of chemotherapy-induced toxicities.

This program was supportedby an unrestricted educational grant from Amgen Inc.

Recent Considerations in Cancer Chemotherapy Toxicity

“Despite advances in the delivery of chemotherapy and the prevention of toxicities, many patients still experience severe toxicity as a result of chemotherapy,” said Amy W. Valley, PharmD, BCOP, clinical assistant professor of pharmacy, Ohio State University, Columbus. Chemotherapy can result in hematologic, gastrointestinal, or end-organ toxicities, each of which can cause response-compromising dose reductions and delays in therapy that may result in patient morbidity and diminished quality of life.

According to Dr. Valley, neutropenia is a dose-limiting toxicity of chemotherapy and is the most common reason for chemotherapy dose reductions and treatment delays. Its other outcomes include infection and hospitalization (more likely with febrile neutropenia), diminished quality of life and economic consequences.

Over the last decade, colony-stimulating factors (CSFs) have been invaluable in reducing the incidence of neutropenia as manifested by febrile neutropenia. According to Dr. Valley, the optimal use of CSF should be evaluated comprehensively in the context of patient’s baseline performance status, tumor type, chemotherapy regimen, previous exposure to chemotherapy and radiation, and overall health status. Traditionally, treatment costs have been high. A study conducted by Lyman and colleagues of 115 large academic institutions from 1995-2000 indicated nearly 80,000 hospitalizations for febrile neutro-penia, with a mean stay of 12 days, and a mean cost of $22,622 (Blood 2001; 98:432a). Recent changes in management of febrile neutropenia, including outpatient management, earlier hospital discharge and the use of oral antibiotics may alter the economics of managing this condition, according to Dr. Valley.

The recent development of pegfilgrastim or Neulasta, which requires just one dose per cycle of chemotherapy (vs. 10 to 11 doses of CSFs such as Neupogen) provides a new option for managing febrile neutropenia. In addition to the advantages associated with once per chemotherapy cycle dosing, preliminary research indicates that there may be other benefits (e.g, altered recovery time) associated with this agent. Future studies to further characterize cost savings and pharmacodynamic benefits, and the potential superiority of pegfilgrastim are needed.

Anemia — the most common hematologic disorder — represents another complication of chemotherapy that can frequently result in patient fatigue and diminished quality of life. According to Dr. Valley, these side effects are both preventable and treatable. A new consideration in the management of anemia in cancer patients is the availability of darbepoetin alfa (Aranesp), which was recently approved for chemotherapy-induced anemia in addition to its indication for anemia related to chronic kidney disease. The prolonged half-life associated with this new compound permits less frequent dosing than the requirements for epoetin alfa. Moreover, preliminary evidence indicates the possibility of faster response time, though additional research is needed. Dr. Valley recommended that practitioners consider the best dosing strategy for darbepoetin alfa, in part by understanding equivalent doses of epoetin alfa and darbepoetin alfa.

While chemotherapy-induced thrombocytopenia does not often result in life-threatening consequences associated with other hematologic toxicities, Dr. Valley explained that oprelvekin (Interleukin-11 or Neumega) is currently used in high-risk patients (though cardiac toxicity and cost limit its use). Potential treatments in developmentinclude thrombopoietin and AMG531, under development by Pharmacia and Amgen, respectively.

Along with advances in the management of hematologic toxicity, new therapies for nausea, vomiting and mucositis are also in development. Preliminary studies demonstrate the efficacy of NK-1 receptor antagonists in combating gastrointestinal toxicity, though some concern exists over resultant infection and febrile neutropenia.

Oral cryotherapy and amifostine (for XRT to the head and neck area) represent potentially effective strategies for the management of chemotherapy-related mucositis. Research regarding several other agents is ongoing.

Dr. Valley pointed out that, for all anti-toxicity remedies, gaps can exist between established institutional treatment guidelines and actual practice. “Many institutions have guidelines in place but few really have gone back to characterize the guidelines and see how well their patients are doing,” Dr. Valley said.

Despite significant progress made in toxicity management in the past decade, Dr. Valley concluded that many issues and questions remain concerning the impact of new agents and the determination of patients most likely to benefit from new treatments. In addition, she emphasized the ongoing need to research, evaluate and quantify the costs of managing toxicities.

New Advancements in the Total Care of Anemia in the Oncology Patient

“Anemia is common in patients with cancer and can occur in up to 50–60% of cancer patients,” said Shane E. Scott, PharmD, BCPS, BCOP, associate professor, Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City; co-director, Clinical Trials Support Care, Holden Comprehensive Cancer Center, University of Iowa. According to Dr. Scott, anemia results when tumor cells and an activated immune system work in tandem to both reduce the number and shorten the survival of red blood cells. (Figure 1)

For many cancer patients, anemia causes symptoms that interfere significantly with daily life. Weakness, fatigue and exhaustion; impaired concentration; decreased cognition; respiratory distress; and tachycardia are commonly experienced. According to Dr. Scott, the severity of chemotherapy-induced anemia is contingent on the nature and extent of the underlying malignancy and the type, schedule and duration of treatment. Other influencing factors include the presence of pre-existing mild anemia, and changes in response to, and production of erythropoietin.

In some cases, chemo-therapy can initially induce a mild anemia that can later develop into a more severe anemia a chemotherapy continues. Some chemotherapy regimens are associated with a higher incidence of anemia when used to treat certain malignancies. While paclitaxel is not necessarily thought of as an anemia-inducing agent, it is associated with over 90% incidence of anemia in metastatic breast cancer, in part resulting from the effects of patients’ prior therapies. In some types of malignancies (e.g., cervical and small cell lung cancers), anemia has been shown to correlate directly with survival and to impact negatively on patient morbidity. Emerging evidence in cervical cancer indicates that anemia may have an impact on survival in these patients (Cancer 2001;92(4):903-908).

Strategies for the management of anemia in cancer patients include individualized treatment aimed at assessing and correcting nutritional deficiencies while treating underlying infections and inflammation, and managing hemolytic disease, occult blood loss, or hemolysis. Transfusion is generally recommended for patients whose anemia is categorized as Grade 3 or 4 (on a four-point rating scale), indicating hemoglobin levels below 8.0. Since the 1990’s, epoetin alfa has been available and was approved to be used in anemia management. This agent has been shown to decrease the rate of transfusions and improve the quality of life and survival of cancer patients by increasing hemoglobin in some patients with anemia of cancer. Recently, a new product, darbepoetin alfa (Aranesp) was approved for the management of chemotherapy-induced anemia. This product increases hemoglobin and alleviates cancer-induced anemia with less frequent dosing based on its longer half-life. Additionally, darbepoetin alfa is approved for anemia associated with chronic renal insufficiency. (Figure 2)

Evidence from various darbepoetin alfa dose finding studies indicates that 3 mcg/kg darbepoetin alfa every two weeks generates equivalent response as once weekly doses of epoetin alfa. At present, various institutions within the medical community have developed their own darbepoetin alfa dosing guidelines, mostly for every two- and three-week regimens. For anemia associated with renal failure and chemotherapy-induced anemia, no single conversion factor can be used, due to the non-linear relationship between rHuEPO and darbepoetin alfa (Aranesp) doses.

Dr. Scott concluded that darbepoetin alfa is an effective agent for treatment of anemia that simplifies the treatment of chemotherapy-induced anemia. Studies have not revealed any differences in side effects between Aranesp and epoetin alfa. Further darbepoetin alfa studies will explore even less frequent dosing schedules, and means of optimizing response and improving outcomes.

Novel Pharmaceutical Approaches for Managing Neutropenia

“Chemotherapy-induced neutropenia is a cause of significant patient morbidity, anxiety and expensive hospitalizations,” said William P. Petros, PharmD, FCCP, associate professor, department of clinical pharmacy, West Virginia University, Morgantown, WV; associate director, Anti-Cancer Drug Development, Mary Babb Randolph Cancer Center, West Virginia University.

Current treatment for neutropenia involving protein biopharmaceutics are associated with limitations that can result in the need for frequent dosing. The pegylation process (adding polyethylene glycol to proteins) can increase the half-life of these proteins from 3- to 400-fold, resulting in several therapeutic benefits. Studies have demonstrated that pegylation prolongs the serum half-life and may decrease immunogenicity. The need for less frequent dosing may translate into increased patient compliance and improved quality of life (From Research to Practice 2001;3:3-9).

According to Dr. Petros, controlling the degree of pegylation is important, to achieve benefits such as decreased renal excretion without impairing bioactivity due to receptor binding. FDA-approved pegylated pharmaceuticals include adnosine deaminase, L-asparaginase, interferon alpha, and recently, filgrastim (G-CSF). Currently, pegylated versions of red blood cells, interleukin 2, liposomal doxorubicin, and TNFr are being investigated.

Recent experimentation with over 40 compounds in the pegylation of filgrastim (an existing neutropenia treatment), resulted in the development of a new molecule (pegfilgrastim) that nearly doubles the molecular weight yet retains essentially identical biologic properties.

Research conducted by Amgen using nephrectomized rats demonstrated that the kidney is no longer an important mechanism of clearance for pegylated filgrastim.

Phase III research conducted by Holmes and colleagues, as well as studies by Green and colleagues indicated no difference in hematopoietic recovery or days of severe neutropenia in patients receiving either a single dose of pegfilgrastim or 11 injections of daily filgrastim. Moreover, research demonstrated no significant difference in adverse effects (including incidence, duration, and severity of bone pain) between filgrastim and pegfilgrastim. No differences were noted when the pegfilgrastim was administered by fixed (6 mg) versus weight-based dosing (100 mg/ kg/day) (J Clin Oncol 2002;20:727-731 and Proc ASCO 2001;20:23a).

Dr. Petros emphasized that the clinical impact of pegylating filgrastim can be dramatic, resulting in a shift from daily to once per cycle dosing. Clinical implications of once per cycle dosing of CSF include increased use of CSFs in situations that were previously too inconven-ient, increased interest in identification of risk factors, expected cost shifting from self-administration to clinic administration, increased patient compliance, and a reduction of patient costs associated with fewer visits, less travel and fewer work absences.

Dr. Petros cautioned about the hazards of concurrent administration of colony stimulating factor (CSF) in continuous infusion or schedule dependent chemotherapy cycles. Previous research conducted by Petros & Crawford demonstrates that severe myelosuppression can result from continuous infusion 5-FU concurrent with growth factor (Curr Opinion Hematol 97;4:213).

Additional research on concomitant dosing is warranted. Future studies are also indicated with regard to other dosing issues, predictive risk models, and the identification of special populations and additional applications (e.g., myeloid malignancies, stem cell transplantation, chronic neutropenia and pediatrics).