Managing Metastatic Breast Cancer Patients Treated with Ixabepilone: Practical Guidance

Cytotoxic chemotherapy is one of the cornerstones for the treatment of metastatic breast cancer (MBC). Drug resistance remains the most common cause of treatment failure; in particular, resistance to anthracyclines and taxanes hinders the management of MBC.¹ With increasing frequency, these agents are being used to treat earlystage breast cancer, meaning that these patients have fewer effective cytotoxic treatment options if they progress to MBC.^1-3 As such, a great deal of active clinical research is focused on developing novel cytotoxics with reduced susceptibility to common drug-resistance mechanisms.

One result of research into novel cytotoxics has been the development of a new class of drugs known as the epothilones. The epothilones have a similar mode of action to taxanes in that they disrupt microtubule function within tumor cells.⁴ The epothilones have a different chemical structure and have demonstrated antitumor activity in patients who have developed resistance to taxanes.^5,6 Ixabepilone is the first epothilone to be approved by the US Food and Drug Administration. Its initial indications are⁷:

• In combination with capecitabine for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane
• As monotherapy for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a taxane, and capecitabine.

In the MBC setting, ixabepilone has been shown to be effective in patients irrespective of their estrogen/progesterone receptor status or their human epidermal growth factor receptor type 2 status.⁸ The recommended dose of ixabepilone is 40 mg/m2 infused intravenously over 3 hours every 3 weeks.⁷

The taxanes have well-characterized side effect profiles. Because ixabepilone and the other epothilones act in a way that is similar to the taxanes, ixabepilone therapy is associated with many of the same side effects that oncology nurses have come to expect during taxane therapy (Table 1). With any new class of agents, however, comes new information and considerations for patient management. Important differences between taxanes and epothilones yield different treatment-specific issues that nurses should understand to help ensure that patients receive the intended benefit from ixabepilone therapy. 

Ixabepilone toxicity profile and appropriate nursing intervention
The most common adverse events seen with ixabepilone used as monotherapy or in combination with capecita bine are presented in Table 1. Other important adverse events that have been associated with ixabepilone include severe hyper sensitivity reactions (HSRs) during drug ad ministration7 and, when ixabepilone is given in combination with cap ecitabine, palmar-plantar erythrod ysesthesia (hand-foot syndrome) and cardiac events.⁷

Side effects during ixabepilone therapy can be effectively managed with dose reduction and supportive care (Table 1). Some common side effects associated with ixabepilone therapy, particularly neutropenia and peripheral neuropathy, can be manageable with proactive intervention but can be debilitating if they progress to severe events. Therefore, nurses can improve treatment outcomes, adherence, and patient quality of life during treatment with ixabepilone by providing information to patients and their families. Patients receiving ixabepilone should be educated as to what to expect during treatment, and they should be alert to signs and symptoms that should be reported to their healthcare team (Table 2). In addition to patient education, specific nursing activities to support patients receiving ixabepilone include monitoring laboratory values, particularly liver function tests, complete blood counts (CBCs), and platelets; assessing for preexisting allergies, administering premedications and monitoring for HSRs during infusions; administering prescribed growth factor support; assessing preexisting neuropathies, and monitoring for new or worsening neuropathy (Table 3).

Pretreatment assessment
Extensive clinical testing has revealed contraindications to ixabepilone therapy, as well as situations under which a lower dose of ixabepilone should be used.^8-11 Even though ixabepilone is not hepatotoxic, patients with preexisting impaired liver function who were treated with the ixabepilone/capecitabine doublet were shown to be at increased risk of toxicity and neutropenia-related death in a pivotal phase 3 trial.⁸ For this reason, ixabepilone plus capecitabine must not be given to patients with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limits of normal (ULN) or bilirubin >1 × ULN. Liver function is also an important consideration for those receiving ixabepilone monotherapy. Hepatic function should be assessed periodically during ixabepilone therapy, with the dose adjusted as necessary.⁷ Before administration of ixabepilone, the nurse should be aware of the current liver function values and check doses accordingly. The following guidelines are listed in the package insert and refer to the first course of therapy; further dose reductions in subsequent courses should be based on individual tolerance⁷:

• AST and ALT ≤2.5 × ULN and biliru bin ≤1 × ULN—administer ixabepilone monotherapy at 40 mg/m2 (full dose)
• AST and ALT ≤10 × ULN and bilirubin ≤1.5 × ULN—administer ixabepilone monotherapy at 32 mg/m2
• AST and ALT ≤10 × ULN and bilirubin >1.5 × ULN to ≤3 × ULN —administer ixabepilone monotherapy at 20 mg/m2 to 30 mg/m2
• AST or ALT >10 × ULN or bilirubin >3 × ULN—use of ixabepilone monotherapy is not recommended.

The CBC and platelets should be checked before the first dose is given and periodically during therapy, because low blood cell counts may preclude the use of ixabepilone or necessitate a dose reduction. As with preexisting hepatic toxicity, patients with a baseline neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3 should not be given ixabepilone.⁷ During therapy, if the neutrophil count is <500 cells/mm³ for ≥7 days, the patient has febrile neutropenia, or the platelet count is <25,000/mm³ (or <50,000/mm³ with bleeding), the dose of ixabepilone should be decreased by 20%.7 A new treatment cycle should begin only when the neutrophil count is ≥1500 cells/mm³ and if nonhematologic toxicities have improved to grade 1 (mild) or resolved.⁷

Preventing HSRs
Like standard formulations of paclitaxel and docetaxel, ixabepilone is formulated HSRs to this vehicle during ixabepilone infusion, patients should be premedicated approximately 1 hour before infusion with both an H1 blocker and an H2 blocker.⁷

Corticosteroid premedication is not mandatory for ixabepilone; in contrast, the taxanes paclitaxel and docetaxel exhibit greater potential for HSRs and steroid premedication is required.^12-14

However, patients who have experienced an HSR in a previous ixabepilone cycle should be premedicated with corticosteroids (eg, dexamethasone 20 mg intravenously 30 minutes before infusion or orally 60 minutes before infusion) in addition to the H1 and H2 blockers. If possible, extending the infusion time should also be considered in these patients. Patients with a history of a severe HSR to agents containing polyethoxylated castor oil should not be treated with ixabepilone.^7,13,14

During the infusion, nurses should closely monitor patients for signs of HSR, including flushing, rash, dyspneaand bronchospasm. Should a severe HSR occur, the ixabepilone infusion should be stopped and aggressive supportive treatment (eg, epinephrine or corticosteroids) started immediately^.7,13

Neutropenia and thrombocytopenia
Nurses should assess patients for myelosuppression frequently during ixabepilone therapy.⁷ With grade 3/4 neutropenia rates of almost 70% with the ixabepilone/capecitabine doublet and around 54% with ixabepilone monotherapy,^8,9 effective management of this side effect is critical for optimizing patient outcomes. Risk factors for neutropenia include older age, bone marrow involvement, immune system dysfunction, hepatic or renal impairment, and malnutrition.^15,16 Patients should be assessed at baseline for these factors to determine whether they are at higher risk, and the treatment team should be informed accordingly.

In patients who develop neutropenia, nurses should watch for symptoms that may increase the risk of or herald infectious complications. These symptoms may be specific to the gastrointestinal system (eg, mucositis and diarrhea), respiratory tract (eg, cough and dyspnea), urinary tract, or indwelling devices, or they may consist of more generalized flulike symptoms (eg, fever, chills, and malaise).¹⁷ It is especially important to educate patients about recognizing and managing febrile neutropenia, and theyshould be strongly advised to seek medical attention immediately if they experience fever, chills, and/or rigors. In addition, patients should be educated regarding steps that can be taken to help minimize the risk of neutropenia, including continuing to eat well and avoiding behaviors and situations that could increase their exposure to infectious agents.¹⁷ Although routine administration of growth factor support is not indicated by the ixabepilone prescribing instructions,⁷ it may be necessary in some patients, and nurses should be aware of the appropriate use of these drugs to maximize their effectiveness. 

Thrombocytopenia is less common than neutropenia in patients receiving ixabepilone, although it was observed in 2% to 6% of patients during the registrational trials.⁷ Therefore, nurses should monitor patients for signs that could indicate this problem, including bleeding from the gums, bruising, petechiae, and blood in the stool or urine. Patients with low platelet counts should not be subjected to intramuscular injections or rectal temperature measurements, and pressure should be applied to venipuncture sites for 5 minutes. Furthermore, enemas and suppositories should be avoided to decrease the likelihood of bleeding.¹⁸

Peripheral neuropathy
Affecting as many as 50% of cancer patients, chemotherapy-induced peripheral neuropathy (CIPN) most likely results from the injury, inflammation, or degeneration of peripheral nerve fibers.¹⁹ CIPN often occurs in a stocking-and-glove distribution pattern, with symptoms originating at the tips of the fingers or toes and progressing toward the trunk. CIPN is a common serious side effect of many cytotoxic agents, and it is a major cause of chemotherapy dose reductions, treatment delays, and discontinuation during ixabepilone therapy.^20,21 In fact, CIPN was the primary cause of treatment discontinuation in the ixabepilone registrational trials.^8,9

CIPN during ixabepilone therapy is primarily sensory, cumulative, and reversible in most patients.21-24 Although the risk of CIPN increases with accumulating exposure to ixabepilone, approximately 75% of cases of new-onset or worsening neuropathy occur within the first three cycles.7 In clinical trials, ixabepilone-associated peripheral neuropathy re solved to baseline or grade 1 within a median of 5.4 weeks after monotherapy and 6.0 to 6.2 weeks after combination therapy with capecitabine.²⁴

To manage CIPN in patients receiving ixabepilone, nurses need to identify preexisting conditions that may affect sensory function and, if necessary, alert the treatment team to the possibility of increased risk of developing CIPN due to preexisting peripheral neuropathy or comorbidities such as diabetes mellitus. ^7,21 In addition, nurses should perform regular neurologic assessments, first to establish baseline neurologic function before treatment begins and then to detect any worsening function in a timely fashion. Patients with stabilization of disease may be less forthcoming with self-reports of CIPN symptoms. A brief assessment that may help reveal symptoms of CIPN may include testing the patient’s ability to button a shirt or pick up objects.²¹ Initiation of a handwriting sample may also be helpful in identifying patients with CIPN. Ad ditional signs of CIPN that should be monitored include a tingling or burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, and neuropathic pain.

Antidepressants, antiseizure medications, and glutamine have demonstrated some success in treating neuropathy once it has developed.^25,26 Most experts agree, however, that the best strategy to minimize the impact of CIPN is early detection coupled with chemotherapy dose reductions and/or delays.^25,27 Accordingly, patients experiencing new or worsening symptoms of CIPN may require a reduction or delay in the dose of ixabepilone, as follows⁷:

• If CIPN is grade 2 (moderate) lasting for ≥7 days or grade 3 (severe) lasting for <7 days—decrease dose by 20%
• If CIPN is grade 3 lasting ≥7 days or is disabling—discontinue treatment.

Several groups are investigating the ability of neurologic tests to detect early neuropathic changes in patients treated with ixabepilone.^21,23 The availability of such tests could theoretically help to prevent the development of severe CIPN, which would be especially valuable in patients with earlier stage disease who might receive ixabepilone in the future.

Ixabepilone administration
At many clinics and private practices, nurses are directly involved in preparing and administering chemotherapy, and therefore, they need to become familiar with the procedures unique to ixabepilone administration. Timing is critical, because a number of ixabepilone administration steps are time-limited. To minimize risk of dermal exposure when handling ixabepilone vials, nurses should wear impervious gloves during unpacking and inspection, transport within a facility, dose preparation, and administration.⁷

Summary
Because ixabepilone has reduced susceptibility to multiple mechanisms of resistance to taxanes and anthracyclines and has proved efficacious in drug-resistant MBC, it provides a much-needed treatment option for patients in whom many other therapies have failed. Oncology nurses should be familiar with the unique aspects of providing ixabepilone therapy, that is, the toxicity profile of which is similar to yet distinct from that associated with taxane therapy. Nurses play a key role in maximizing the clinical benefit of ixabepilone therapy and encouraging adherence, so that patients may achieve optimal outcomes.

Acknowledgments
The author takes full responsibility for the content of this publication and confirms that it reflects her viewpoint and medical expertise. She also wishes to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editing support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the author receive financial compensation for authoring the manuscript.

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