Oral therapy: Managing side effects can aid adherence
Anticancer therapy has increasingly shifted away from traditional intravenous chemotherapy toward greater use of oral cancer therapies, significantly increasing convenience and independence for patients. As a result, patients need to commute to the clinic for treatment less frequently and avoid potential complications associated with IV injections, hence experiencing improved quality of life. However, oral therapy has made monitoring side effects, and adherence and persistence with therapy, more problematic.1,2 These are critical issues, especially with targeted therapies, because patients often need to continue treatment for years. The potential for nonadherence and nonpersistence is increased over a longer term.
One oral targeted therapy that has changed clinical outcomes for patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) is imatinib (Gleevec).3,4 The agent is administered as a daily regimen and has a generally manageable toxicity profile, yet adherence is not ideal.5 This article discusses GIST treatment with imatinib and how nurses can improve treatment adherence, persistence, and clinical outcomes of oral anticancer therapy by promoting patient education and timely reporting and management of adverse effects.
AN OVERVIEW OF GIST
Gastrointestinal stromal tumors are rare, compared with other cancers, but are nonetheless the most common mesenchymal tumors in the GI tract.6 A Swedish study approximated prevalence at 129 cases per million population in western Sweden; in the United States, new cases are estimated at 6,000 or fewer per year.7,8
Approximately 85% to 90% of GIST contain activating mutations in the tyrosine kinases (KIT) or platelet-derived growth factor receptor alpha (PDGFRA), thus contributing to the pathophysiology of the tumor.4 The remaining 10% to 15% of tumors do not have mutations in KIT or PDGFRA and are called wild-type. Other cellular pathways are deregulated, however, causing GIST.
Localized, resectable primary GIST Surgery is recommended for all primary tumors 2 cm or larger.4 However, even with complete resection, approximately 50% of patients experience recurrence.9 Imatinib is a tyrosine kinase inhibitor (TKI) that targets KIT and PDGFRA. It is indicated as first-line adjuvant therapy for the treatment of GIST following surgical resection of the primary tumors.5 In a phase III clinical trial, adjuvant imatinib (400 mg/day) significantly improved recurrence-free survival (RFS) in patients who underwent surgical resection of gastrointestinal stromal tumors 3 cm or larger compared with placebo (1-year RFS, 98% vs. 83%, respectively).10
Adjuvant imatinib was particularly effective in high-risk patients (those with tumors 10 cm or greater), showing an overall survival benefit with 3 years of treatment compared with 1 year (92% vs. 82%, respectively).10,11 Therefore, even though the optimal duration of treatment with imatinib for nonprogressing GIST has not yet been defined, the National Comprehensive Cancer Network (NCCN) guidelines recommend considering 3 years of adjuvant therapy for patients with intermediate- to high-risk GIST to reduce the risk of recurrence.12 An ongoing clinical trial (PERSIST) is investigating the benefits of 5 years of adjuvant therapy in high-risk patients (NCT00867113).13
Advanced/metastatic GIST Imatinib is also indicated for unresectable or advanced/metastatic GIST, starting with 400 mg/day until disease progression.4,5 This recommendation is based on results from the B2222 trial, which showed a 5-year overall survival rate of 68.1% in patients treated with imatinib, regardless of the dose they received (400 vs. 600 mg/day).14 A subsequent trial (the BFR14 trial) showed that patients with advanced GIST who discontinued imatinib therapy after 3 years had a much lower progression-free survival rate (16%) than those who continued therapy (80%), pointing to the importance of adherence and persistence with treatment.15 A meta-analysis of two phase III clinical trials of imatinib at 400 and 800 mg/day in patients with unresectable/metastatic GIST showed that patients with KIT exon 9 mutations benefited from the higher dose, whereas patients without exon 9 mutations did not.16 Based on these data, the NCCN Task Force recommends that patients who are responding or experiencing stable disease continue therapy.4 If disease progression occurs while the patient is taking 400 mg/day, treatment can continue with the same dose, the dose can be increased to 800 mg/day, or treatment can be switched to sunitinib (Sutent).4
Neoadjuvant treatment Although not FDA-approved for this usage, imatinib may be administered as neoadjuvant therapy to downstage GIST and facilitate resection or to reduce surgical morbidity of resectable GIST.4 The RTOG 0132/ACRIN 6665 clinical trial investigated the efficacy and safety of neoadjuvant therapy with imatinib (600 mg/day for 8 weeks) in patients with potentially resectable primary or recurrent/metastatic disease.17 In this setting, estimated 2-year progression-free survival and overall survival were 82.7% and 93.3%, respectively, in patients with primary disease vs 77.3% and 90.9%, respectively, in patients with advanced disease.17 These results compare advantageously to the historical median progression-free survival of 7 to 20 months and demonstrate the potential benefits of imatinib as a neoadjuvant agent.4
ADHERENCE AND PERSISTENCE
Medication adherence and persistence are different issues.18 Adherence refers to compliance with a prescribed or recommended treatment, with respect to timing and dosing. In that regard, under- and over-medication both result in nonadherence. Persistence, on the other hand, refers to continuing treatment over time from start to end of therapy.
Adherence and persistence are complex; they depend on factors that can be disease- or patient-related, such as depression, forgetfulness, asymptomatic disease, adverse effects, infrequent follow-up, complexity of treatment, medication cost, age, polypharmacy, and lack of knowledge.2,4,19 In general, studies on oral cancer therapies report adherence rates ranging from 17% to 100%.20-28 Information on adherence to imatinib therapy in GIST is limited; however, one study showed an overall adherence rate of 73% (defined as the apparent mg taken:mg prescribed ratio), but only 50% of patients were 100% adherent, taking the correct dose at the correct time.29 In the same study, persistence (measured as time on prescription without significant gaps between refills) only averaged 255 days over 24 months.29
Suboptimal adherence and persistence are a concern as they may lead to reduced therapeutic effectiveness. Indeed, interruption of imatinib treatment has been shown to result in rapid progression of GIST (within 6 to 12 months).10,30 Another study found that patients with suboptimal clinical response had significantly higher amounts of untaken drug.31 Under-medication may limit the effectiveness of imatinib, as its elimination half-life is 10 to 20 hours.32,33 In contrast, over-medication (eg, taking multiple doses to compensate for a missed dose) could increase toxicity and adverse effects.2
MANAGING ADVERSE EFFECTS TO IMPROVE ADHERENCE
Adverse effects from imatinib treatment are most prevalent in the first 8 weeks of treatment, generally mild to moderate, and manageable without treatment interruption or dose reduction.34,35 In addition, they tend to improve over time and resolve after discontinuation.4,34 Adverse effects are similar at both 400 and 800 mg/day and, except for edema, the incidence of grade 3 or greater adverse effects is similar. Moreover, many of the adverse effects reported in clinical trials of long-term therapy at 400 mg/day are similar in grade and occurrence to those reported with placebo, indicating that the adverse effects may be related to the underlying disease.10,34