Ixabepilone: an Epothilone for the treatment of Metastatic Breast Cancer
Breast cancer is the most common cancer affecting women in the United States. It was estimated that 178,480 women would be diagnosed with breast cancer in 2007 with approximately 2,030 cases diagnosed in men. Breast cancer ranks second, behind lung cancer, for cancer mortality in the United States. Despite advances in early diagnosis and treatment, approximately 40,910 deaths will be attributed to breast cancer in 2008. Therefore, continued investigation into better treatments for breast cancer is imperative. This program will describe a new class of anti-neoplastic agents known as epothilones and review the pivotal data leading to the approval of ixabepilone (Ixempra®) for the treatment of metastatic breast cancer.
Breast cancer mortality has declined in the United States since 1990. This decline in patient deaths from metastatic breast cancer is thought to be related to improvements in knowledge about early detection, participation in screening through mammography, and increases in the number and efficacy of hormonal and anti-neoplastic agents available for the treatment of metastatic breast cancer. Taxanes are thought to account for much of the improvement in survival.
Overview of Metastatic Breast Cancer
When a woman is originally diagnosed with breast cancer, many aspects of her original tumor are examined to determine her prognosis, which means the likelihood that her breast cancer will recur following definitive surgical therapy. Pathologic prognostic indicators include the size of the original tumor, the presence of lymph node involvement, the extent of lymph node involvement if present, hormone receptor status (estrogen and progesterone receptor positivity or negativity), Her-2-neu status, nuclear grade, histologic subtype, mitotic rate, and the presence of lymphatic or vascular invasion. These indicators are also used to determine the need for additional or adjuvant therapy prior to or following definitive surgery which might include chemotherapy, hormonal or biologic therapy. Newer therapeutic indexes such as Oncotype Dx and Mammoprint can be used as well to assess a woman’s recurrence risk. In the adjuvant setting, when chemotherapy is deemed useful, options often include the use of an anthracycline and a taxane.
When a woman is first diagnosed with metastatic breast cancer, the goal of curing her of breast cancer is not currently realistic; however, due to the multitude of options available for the treatment of metastatic disease, it can currently be thought of a chronic disease which may require multiple courses of varying therapies for its treatment. The treatment goals therefore are threefold. First, the goal of therapy is to palliate symptoms, ensuring an adequate and satisfying quality of life. Second is to prolong survival. Third is to prolong the time until disease progression. All three of these treatment goals are included as endpoints in clinical trials evaluating new therapies for the treatment of metastatic breast cancer.
There are several options for treatment when a woman presents with metastatic disease. Again, symptom palliation and therefore supportive care remains a primary focus. Additional agents which may be considered include endocrine or hormonal therapies, chemotherapy agents, and biologically targeted agents. Endocrine options include selective estrogen response modifiers such as tamoxifen and fulvestrant (Faslodex®), aromatase inhibitors such as anastrozole (Arimidex®), exemestane (Aromasin®), letrozole (Femara®), as well as mechanisms for ovarian suppression. Chemotherapy options include taxanes, such as paclitaxel (Taxol®), docetaxel (Taxotere®), and albumin-bound paclitaxel (Abraxane®). Other chemotherapeutic options include anthracyclines; capecitabine, gemcitabine, and navelbine. Biologic agents targeting the her-2 receptor include trastuzumab (Herceptin®) and lapatinib (Tykerb®). Other biologically targeted agents may be used in metastatic breast cancer. Like chemotherapy agents, these agents can be used alone or in combination with other therapies.
When determining the most appropriate therapy for a patient, many factors must be considered. Is the breast cancer hormone receptor positive, making endocrine therapy an option? Is the patient pre-menopausal or post-menopausal? Does the patient have multiple sites of visceral disease? Is the patient symptomatic from her breast cancer? What has the disease free interval been? What is the patient’s functional status? These questions must be considered when a patient first presents with metastatic disease and any time a change in therapy is being considered.
Principles of Therapy in Metastatic Breast Cancer
When a cancer cell undergoes cell division, like any other cell in the body, the chromosomes which contain all of the genetic material, or DNA, in the cell must first be replicated. After this complex process is completed, two identical daughter cells are formed. The original strand of DNA is separated by a special enzyme known as topoisomerase. This results in two single strands of DNA which are then replicated creating two identical strands of DNA which form chromosomes. During DNA replication nutrients are converted into nucleic acids, the building blocks of DNA, and are then incorporated into the new identical strand of DNA. At any point of this duplication process, other agents can form bonds with either strand of DNA to prevent its replication. Repair mechanisms are present within the cell to attempt to eliminate this disruption. Once two identical chromosomes have been created, they align themselves in the center of the cell and are then pulled into one of the two identical daughter cells by microtubules. Chemotherapeutic agents work by interfering with various parts of the cell cycle.
Anti-metabolites such as methotrexate or gemcitabine inhibit cell division by substituting themselves for the metabolites that are normally converted into nucleic acids. Without the necessary nucleic acids that would be incorporated into the new strand of DNA, cell division cannot take place resulting in cell death or apoptosis. Topoisomerase inhibitors such as Irinotecan block the enzyme needed to separate the original strands of DNA, inhibiting DNA replication and therefore cell division. Alkylating agents such as doxorubicin or epirubicin cause damage directly to the DNA strands. These drugs bind tightly to the DNA and are resistant to normal cell repair mechanisms. Microtubules are affected by many different chemotherapy drugs. Vinca alkaloids such as vinorelbine act to destabilize microtubules and inhibit the separation of DNA into the two daughter cells, resulting in apoptosis. Taxanes such as paclitaxel or docetaxel work to stabilize the microtubules also preventing the separation of the replicated chromosomes into the two daughter cells, leading to apoptosis. Chemotherapeutic agents that work on different steps in the cell division pathway are often combined to enhance the ability to cause cell death. However, combining chemotherapy agents often leads to greater toxicities, which is of concern in patients with metastatic disease where quality of life is a primary goal.
Despite the multitude of mechanisms that anti-neoplastic agents have to cause cancer cell death, some cancer cells develop mechanisms to resist the effects of those agents. These cancer cells are described as demonstrating multi-drug resistance, which is often accomplished by the cell through an efflux pump known as p-glycoprotein.
Current Treatments for Metastatic Breast Cancer
Anthracyclines are commonly used to treat breast cancer; these include doxorubicin, liposomal doxorubicin, and epirubicin. Anthracyclines interrupt cell division by binding to DNA and causing damage directly to the DNA strands. These drugs can be used alone or in combination chemotherapy regimens with a variety of other antineoplastic agents.
Capecitabine is an anti-metabolite; it was approved in 1998 as single agent for the treatment of metastatic breast cancer in patients who were refractory to an anthracyline and a taxane. The response rate was 20% in these patients. It was approved for use in combination with docetaxel in 2001 for patients with metastatic breast cancer who were resistant to an anthracycline, with a response rate of 42%.
Navelbine, a vinca alkaloid, is a microtubule destabilizing agent approved for use in patients with metastatic breast cancer as a single agent. Response rates vary from 35-59% in first line therapy to 16% in patients previously treated with an anthracycline and a taxane.
Gemcitabine is an anti-metabolite approved for treatment of patients with metastatic breast cancer in combination with paclitaxel who have progressed following an anthracyline.
Trastuzumab is biologic agent, directed against her-2, approved for use as monotherapy and in combination with paclitaxel in patients with metastatic breast cancer who overexpress the her-2 receptor protein. Lapatinib is a biologically targeted agent that is approved for use in combination with capecitabine in her-2 positive patients who have progressed on trastuzumab, an tetracycline, and a taxane.
Overview of Epothilones
Epothilones, like several other groups of anti-neoplastic agents work on the microtubules. Microtubules are the "skeletons" of cells and must be broken down in order for a cell to divide or reproduce. Like taxanes, emotions work by stabilizing microtubules, which prevents the cell from dividing or reproducing, ultimately leading to cell death or apoptosis. Emotions are naturally occurring macro ides. The currently approved ixabepilone is derived from the myxobacterium soragium cellulosum, which is naturally found in African soil.
In vitro studies demonstrated the efficacy of ixabepilone in cancer cell lines previously demonstrated to be taxane-resistant. There are more than 300 epothilones currently under investigation for use in cancer. Two agents, ixabepilone and deoxyepothilone (KOS-862) have completed Phase II clinical trials in breast cancer. Ixabepilone (Ixempra ®) was approved for use in metastatic breast cancer patients in October 2007. It is indicated as a single agent in patients with metastatic breast cancer who have progressed on an anthracycline, taxane, and capecitabine and it is indicated for use in combination with capecitabine in patients with metastatic breast cancer who have progressed on an anthracycline and a taxane.
Epothilones work by binding directly to the β-tubulin subunit on the microtubules and demonstrate the ability to overcome multi-drug-resistance mechanisms, including the p-glycoprotein efflux pump which is thought to confer taxane resistance.
Ixabepilone was studied as monotherapy in four completed Phase II clinical trials evaluating various dosing schedules and infusion times. The Phase II trial that led to its approval as monotherapy enrolled 126 women with locally advanced or metastatic breast cancer that was resistant to an anthracycline, taxane, and capecitabine. The overall response rate was 11.5%, while stable disease was seen in 50% of patients. In first line therapy, response rates have been reported as high as 41.5-57%. A Phase III trial was completed that combined ixabepilone with capecitabine. It enrolled 752 women with metastatic breast cancer that was resistant to anthracycline and a taxane. The overall response rate with the combination was 35% versus 14% with capecitabine alone. Progression free survival was also extended from 4.2 months to 5.8 months (Vahdat et al, 2007).
Deoxyepothilone also completed a Phase II trial in patients with metastatic breast cancer resistant to an anthracycline and a taxane. Twenty percent of patients in this trial responded to therapy (Overmoyer, et al, 2005).
Toxicities associate with Epthothilones
The main side effects seen with ixabepilone included peripheral neuropathy, myelosuppression, hepatic impairment, and hypersensitivity reactions.
Peripheral neuropathy was common, occurring in 63% of patients treated with ixabepilone alone and 67% of patients treated with ixabepilone plus capecitabine; grades 3 and 4 peripheral neuropathy occurred in 14% of patients treated with monotherapy and 23% of patients treated with the combination. After discontinuation of the therapy with ixabepilone, peripheral neuropathy symptoms returned to baseline within 12 weeks in 79% of patients treated with monotherapy and 76% of patients treated with the combination. The mean time to resolution was 4.6 weeks in the monotherapy study and 6.0 weeks in the combination therapy study.
Myelosuppression primarily manifested as neutropenia, which occurred in 23% of patients treated with monotherapy and 36% of patients treated with the combination. Febrile neutropenia occurred in 3% of patients treated with monotherapy and 5% of patients treated with combination therapy.
Ixabepilone in combination with capecitabine is contraindicated in patients with baseline hepatic impairment since the risk of all toxicities and febrile neutropenia was found to be greater in that group. Risk of toxicity was also greater in patients treated with monotherapy, although single agent ixabepilone is not contraindicated in that group of patients. Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT > 2.5 times the upper limit of normal or a bilirubin > 1 times the upper limit of normal. Dosage modifications should be made in monotherapy administration for any patients with mild or moderate hepatic impairment.
Lastly, because ixabepilone is formulated with Cremophor, hypersensitivity reactions can occur. Only 1% of patients treated with ixabepilone experienced hypersensitivity reactions. All patients should be pre-medicated with both a H1 (diphenhydramine) and a H2 (Zantac, tagamet) antagonist. Three of the nine patients who experienced HSR were able to be retreated with the addition of a corticosteroid to premedication.
Other toxicities include fatigue/asthenia (weakness), arthralgias/myalgias, alopecia, nausea/vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain.
Ixabepilone is approved for administration at 40 mg/m 2 IV over 3 hours every 21 days. Patients should be pre-medicated with a H1 and a H2 blocker at least 30 minutes prior to administration. Ixabepilone should be reconstituted with the supplied diluent. Any further dilution must be with Lactated Ringers Solution. The infusion must be completed within 6 hours of final dilution through an appropriate in-line filter with a microporous membrane of 0.2-1.2 microns. DEHP-free infusion containers and administration sets must be used for the infusion.
Since peripheral neuropathy is common complication of epothilone therapy, all patients should have a baseline assessment of their neurologic function and should undergo routine assessment prior to each dose. If grade 2 peripheral neuropathy persists longer than 7 days, a 20% dose reduction should be instituted. Patients experiencing grade 3 peripheral neuropathy lasting less than 7 days should also receive a dose reduction of 20%. If grade 3 peripheral neuropathy persists longer than 7 days, ixabepilone should be discontinued.
Various clinical tools can be utilized to document neurotoxicity including the NCI common toxicity criteria, the Mini-Mental status examination, Jebson Test of Hand Function, and the Grooved Peg Board Test, to name a few. As part of the baseline assessment, evaluation of all other medical conditions should be documented and considered including prior chemotherapy exposure, history of diabetes or neuropathies and age.
For patients who do experience peripheral neuropathy, supportive measures should be instituted. Pain can managed with narcotic and non-narcotic pain medications and neuroprotectant agents, such as gabapentin, pamelor, elavil and pregabalin, can be instituted if appropriate. No agents have been identified to correct or prevent peripheral neuropathy, although many clinical trials are currently underway addressing this issue. Safety can be an issue for patients with neuropathy and referral to a physical or occupational therapist may be appropriate. Patients should also be reminded of safety issues, including decreased temperature sensitivity, using caution on steps and walking at night, and to check their feet daily for the development of any sores.
Hypersensitivty reactions occur because of a reaction of the immune system to the agent infused or the diluent. These reactions are characterized by nausea, vomiting, flushing, bronchospasm, shortness of breath, rashes, urticaria, angioedema, back pain, alterations in blood pressure and heart rate. Hypersensitivity reactions to epothilones should be managed in the same manner that other hypersensitivity reactions are treated. Due to the risk of these reactions, patients should be pre-medicated with both a H1- and a H2-blocker one hour prior to the infusion. If a patient begins to experience these symptoms, the infusion should be stopped immediately and basic life supporting steps should be initiated to maintain airway, breathing, and circulation. Supportive care should include oxygen, corticosteroids, epinephrine, H2-blockers and IV fluid, among others.
Patients with a history of a hypersensitivity reaction to cremophor (as is used in paclitaxel) or its derivatives should not be treated with ixabepilone. In clinical studies with ixabepilone, only 1% of patients experienced severe hypersensitivity reactions. One third of those patients were able to be retreated; however, patients who experience a hypersensitivity reaction should be pre-medicated with corticosteroids in addition to the H1- and H2-blocker in all subsequent cycles. Extension of the infusion time should also be considered.
Myelosuppression resulting from ixabepilone is primarily manifested as neutropenia. Grade 4 neutropenia (ANC < 500 cells/mm 3) occurred in 36% of patients receiving ixabepilone in combination with capecitabine and 23% of patients treated with monotherapy. Febrile neutropenia was rare, affecting 5% of patients treated with the combination and 6% of patients treated with monotherapy. In patients with normal to mild impairment of liver function treated with the combination of ixabepilone and capecitabine, the rate of neutropenia-related death was 1.9% compared with 29% of patients with pre-existing hepatic impairment. Patients with hepatic impairment should not be treated with the combination of ixabepilone and capecitabine. In patients treated with monotherapy, only 0.4% experienced neutropenic fever.
Patients should have an absolute neutrophil count greater than 1500 cells/mm 3 prior to receiving ixabepilone and a platelet count greater than 100,000 cells/mm 3. Dose reductions by 20% should be instituted for all patients who experience grade 4 neutropenia lasting longer than 7 days, febrile neutropenia, platelets less than 25,000 cells/mm 3 or platelets less than 50,000 cells/mm 3 associated with bleeding.
Other side effects that require appropriate nursing interventions include nausea, vomiting, diarrhea, mucositis and stomatitis. Patient education remains the cornerstone to providing safe and effective care for patients with metastatic breast cancer.
Nursing Considerations for the patient receiving an Epothilone
There are a large number of women diagnosed with breast cancer in the United States each year. While many of the cases of diagnosed breast cancer are found in an early stage, a high percentage of women will go on to develop metastatic disease. All nurses who care for women with metastatic breast cancer should be aware of the current treatments available for use in this patient population. Ixabepilone, and perhaps other epothilones in the near future, can be a treatment option for these women. Nurses who care for patients receiving epothilones should be aware of the various infusion times and schedules for each drug. They should also be aware of the diluent used to reconstitute each epothilone and the pre-medications required for each drug. Additionally, they must be able to provide adequate education to the patient receiving an epothilone about possible side effects, including hypersensitivity reaction, and times to call their provider’s office. Nurses should also familiarize themselves with the tools available to measure neurologic function and specifically peripheral neuropathy.
Many clinical trials are currently underway to examine the safety and efficacy of other epothilones as well as the ability to combine epothilones with other well established agents used for the treatment of metastatic breast cancer.
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