Current management of patients with gastrointestinal stromal tumor receiving the multitargeted tyrosine kinase inhibitor sunitinib.

Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2015.1045470

Vol. 31, No. 7, 2015, 1363–1376

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Brief review Current management of patients with gastrointestinal stromal tumor receiving the multitargeted tyrosine kinase inhibitor sunitinib

Amy Potter Pilotte Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Rhode Island Hospital Comprehensive Cancer Center, Providence, RI, USA Address for correspondence: Amy Potter Pilotte, ANP-BC, Rhode Island Hospital’s Comprehensive Cancer Center at East Greenwich, 1454 South County Trail, East Greenwich, RI 02818, USA. Tel: +1 617-549-2975; [email protected] Keywords: GIST – Sarcoma – Side-effect management – Sunitinib – Tyrosine kinase inhibitors Accepted: 23 April 2015; published online: 5 June 2015 Citation: Curr Med Res Opin 2015; 31:1363–76

Abstract Background: Gastrointestinal stromal tumor (GIST), a form of soft tissue sarcoma, is often detected incidentally or at an advanced stage. The tyrosine kinase inhibitor sunitinib malate (Sutent*) is established as second-line treatment for the management of GIST after disease progression on, or intolerance to, first-line imatinib treatment. Several published reviews give guidance on management of side effects in patients with advanced renal cell carcinoma treated with sunitinib, but fewer publications cover side-effect management in patients with GIST. Scope: Using published articles and abstracts, prescribing information, and personal experience in managing patients with GIST at a specialized center of excellence for cancer care, I review side-effect management recommendations for patients with GIST treated with sunitinib and provide an overview of GIST. Findings: Sunitinib has a well described side-effect profile: most side effects occurring in patients with GIST can be easily managed by standard medical intervention and/or dose modification. Conclusion: Care of patients with GIST can be enhanced through communication, support, knowledge, and education, with the goal of providing effective therapy and optimal symptom control.

Introduction Effective management and treatment of patients with gastrointestinal stromal tumor (GIST) requires the coordinated efforts of a multidisciplinary healthcare team. Indeed, the availability of practical current guidelines endorsing such an approach1 has led to an increasing awareness of this rare disease and greater confidence in managing patients, to the extent that GIST is now more commonly treated, at least initially, in the community. Here I review the use of the multitargeted receptor tyrosine kinase inhibitor (TKI) sunitinib malate (Sutent*) for the treatment of GIST, with a focus on management of side effects. *Sutent is a registered trade name of Pfizer Inc., New York, NY, USA

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Sunitinib treatment management in GIST Pilotte

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GIST overview


Pathology and pathogenesis GIST, a form of soft tissue sarcoma, is the most common mesenchymal neoplasm of the gastrointestinal tract. GISTs arise most commonly in the stomach (50%), followed by the small intestine (25%), and colon and rectum (10%), and approximately 10% are located in the mesentery, omentum, retroperitoneum, and pelvis2. The tumors range in size from under 1 cm to more than 35 cm2. At presentation, approximately 10% of GISTs have invaded the surrounding structures3 and, depending on the series, 16–47% of patients present with clinically evident metastatic disease4,5. Tumors tend to metastasize to the liver or disseminate throughout the peritoneal cavity. Extra-abdominal spread is less common, and metastasis to the bone or lungs is exceedingly infrequent4,6. Metastasis rarely occurs via the lymphatic system3. It is now recognized that approximately 80% of GISTs bear activating mutations in the gene encoding the receptor tyrosine kinase (RTK) known as KIT7. These mutations result in the constitutive activation of KIT signaling, ultimately leading to increased tumor cell survival (anti-apoptosis) and cellular proliferation. At initial presentation tumors from any single patient have only one mutation in the KIT gene, most commonly in the exon 11 region of the gene; however, some patients have tumors with mutations in exons 9, 13, 17, or other locations. This is important because the mutation type has been reported to have prognostic and predictive impact in this disease and to be relevant for the action of molecular-targeted therapy with TKIs such as imatinib or sunitinib7. In another 5–8% of patients, GIST is associated with activating mutations within the gene encoding the structurally similar RTK platelet-derived growth factor receptor alpha (PDGFRA)7. KIT and PDGFRA mutations are mutually exclusive. In 12–15% of patients, no mutations in either gene are found (these cases are termed ‘wild-type GIST’), and the molecular basis of this form of the disease remains unclear7. In a very rare group of wild-type GIST patients, mutations in genes encoding subunits of the Krebs cycle enzyme succinate dehydrogenase have been described8, although the exact mechanism by which these alterations cause GIST is unclear.

Presentation and prognosis An estimated 4000–6000 new GIST cases are diagnosed annually in the United States9,10. GIST may be slightly more common in men, and the median age at diagnosis is 55–60 years6. 1364


GIST is most often asymptomatic but, if any symptoms are present, they are generally nonspecific and relate to the site of the tumor. Smaller GISTs tend to be asymptomatic and are found incidentally during surgery or endoscopy for other conditions. Patients with larger tumors commonly present with vague abdominal discomfort or pain, a palpable abdominal mass, early satiety, and fatigue related to anemia2,11. Gastrointestinal bleeding may be associated with large GIST lesions, especially with mucosal ulceration. GIST may also be associated with bowel obstruction or perforation, dysphagia, fever, and obstructive jaundice11. Tumor size and mitotic index are generally accepted independent predictors of prognosis in patients with GIST9. Revised risk assessment guidelines for GIST now also include anatomic location because GISTs of the small intestine and rectal region are associated with a higher risk of progression and recurrence than gastric GISTs of similar size and mitotic activity2,12.

Treatment of GIST GIST diagnosis and treatment requires a multidisciplinary approach involving various healthcare professionals, ideally trained in the management of sarcoma1,13. However, as noted above, GIST is increasingly managed in the community, at least initially, as practitioners have become more comfortable with the approved treatments and their side effect profiles.

Surgery for localized GIST Surgery is the mainstay of treatment for primary, localized, resectable GIST. The goal of surgery is complete tumor removal without rupture and, if possible, with a tumor-cell-free tissue margin, while optimizing the patient’s functional outcomes. Even after surgery, patients are at significant risk of relapse and eventual death due to disease recurrence and metastases14: complete resection of a localized, primary GIST is associated with a recurrence rate of approximately 35%, and the recurrence rate is 90% in patients with locally advanced or disseminated disease15. The median time to relapse for a resected, primary, high-risk GIST is approximately 2 years1. International guidelines recommend that, where such facilities are available, mutational analysis be used to determine GIST genotype as part of the diagnostic process, and may be particularly useful for KIT-negative GISTs1,13.

Imatinib adjuvant therapy for resectable GIST The fact that GIST is a disease driven by an uncontrolled RTK (either KIT or PDGFRA, depending on the patient) www.cmrojournal.com ! 2015 Informa UK Ltd



led to the rational application of medicinal chemistry to develop drugs that block the enzymatic activity of uncontrolled mutationally activated kinases. These drugs, TKIs, have revolutionized the management of GIST. The use of the selective TKI imatinib at a dose of 400 mg/day for at least 1 year as adjuvant therapy after complete gross resection of KIT-positive GIST has been shown to reduce the risk of GIST recurrence when compared with placebo: recurrence-free survival with imatinib at 1 year was 98% versus 83% with placebo (P50.0001)16. More recently, statistically significant improvements in recurrence-free survival and overall survival were demonstrated for 36 months versus 12 months of adjuvant imatinib treatment in patients with a high risk of GIST recurrence after surgery17. Based on these data, imatinib was approved in the US for adjuvant treatment of adult patients following complete gross resection of KIT-positive GIST18. The optimal duration of imatinib adjuvant therapy remains an area of active investigation, and several trials testing various dosing schedules are underway.

TKI therapy for metastatic or unresectable GIST Imatinib 400 mg/day is approved by regulatory agencies worldwide for the first-line treatment of KIT-positive unresectable and/or metastatic GIST18. A dose of 800 mg/day is an option for patients with KIT exon 9 mutations (who have shown superior disease control on the higher dose) and for patients whose disease progresses on the lower dose1,13. Although imatinib is a highly effective therapy for GIST, 10–14% of patients show primary resistance to this drug and more than 50% develop secondary (acquired) resistance within approximately 2 years of starting treatment19,20. Acquired resistance often correlates with the appearance of secondary mutations in the KIT or PDGFRA genes21,22. The multitargeted TKI sunitinib is approved as the standard second-line therapy for metastatic or unresectable GIST after disease progression on, or intolerance to, imatinib1,13,22. Continued treatment is recommended for as long as benefit is seen with TKIs, although resistance eventually occurs in nearly all patients with advanced GIST23. A third TKI, regorafenib, was approved by the FDA in 2013 for the treatment of patients with unresectable GIST that no longer responds to imatinib or sunitinib24. Regorafenib has activity against multiple targets, including KIT, PDGFR, vascular endothelial growth factor receptors (VEGFRs), and intracellular kinases that promote cancer growth25, and has shown additional benefit in the highly refractory population of patients with metastatic or unresectable GIST that has progressed on imatinib and sunitinib26. With a similar side effect profile to sunitinib, ! 2015 Informa UK Ltd www.cmrojournal.com

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it is expected that experience with the more established treatment will contribute to a better understanding of how these agents are managed in patients with GIST, and ultimately to better outcomes overall.

Sunitinib for the treatment of GIST Sunitinib is an oral multitargeted TKI with antiangiogenic and antitumor activity resulting from blockade of several RTKs, including KIT, PDGFRs, and VEGFRs22. The approved sunitinib dosing schedule is 50 mg/day for 4 weeks followed by 2 weeks off treatment in 6 week cycles (Schedule 4/2). However, many GIST patients and clinical experts prefer to dose sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day without stopping treatment) to avoid symptomatic disease ‘flares’ that can occur during the off-treatment period of Schedule 4/2. The efficacy and safety of sunitinib in the treatment of GIST patients following progression on or intolerance to imatinib has been demonstrated in several clinical trials. Table 127–33 summarizes the design of these studies and the efficacy results obtained. Observations regarding safety and tolerability, with implications for nursing and patient support, are described in detail below.

Safety and tolerability: sunitinib 50 mg/day, intermittent Schedule 4/2 Sunitinib therapy is associated with a well described adverse event (AE) profile across all clinical trials in GIST27,29–33. AEs were generally managed using standard supportive medical therapies, dose reduction, and/or dosing interruption. Long-term experience with sunitinib 50 mg/day on Schedule 4/2 has been reported for two trials: a randomized, double-blind, placebo-controlled phase III study and a large open-label treatment-use study offering access to sunitinib to patients who are ineligible to participate in sunitinib clinical trials or for whom sunitinib is unavailable prior to regulatory approval in their country (Table 1)30–32. The phase III study was unblinded early at a planned interim analysis due to efficacy (Table 1)29, and all patients were offered the opportunity to receive openlabel sunitinib. In the final analysis of the phase III study, among patients who received blinded and/or openlabel sunitinib across the entire trial (n ¼ 241; median six treatment cycles started), 42% required dosing interruptions, 36% due to AEs30. In addition, 28% of patients on sunitinib had dose reductions. Most toxicities were mild to moderate in severity (Table 2)30. Throughout the entire study, as in the double-blind phase, the most common treatment-related non-hematologic AEs among patients receiving sunitinib were fatigue, diarrhea, and nausea, with frequencies of 47%, 43%, and 37%, respectively. Sunitinib treatment management in GIST Pilotte

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Patients randomized 1:1 to morning or evening dosing of sunitinib 37.5 mg/ day

Demetri et al. (2006)29 Demetri et al. (2012)30

Reichardt et al. (2015)31 Reichardt et al. (2011)32

George et al. (2009)33

As of November 2011: – median TTP: 8.3 months – median OS: 16.6 months Long-term clinical benefit of sunitinib treatment confirmed in broad population of GIST patients rather than controlled clinical trial population Clinical benefit rate: 53% (13% PRs, 40% SD 24 weeks) Median PFS: 34 weeks Median OS: 107 weeks Sunitinib (37.5 mg) on CDD schedule appears to be an alternative dosing strategy Sunitinib antitumor activity similar with morning or evening dosing

Demetri et al. (2009)27

Reference

At interim analysis, median TTP with sunitinib (27.3 weeks) 44-fold as long as with placebo (6.4 weeks; P5.0001); trial unblinded early Patients on placebo could transfer to openlabel sunitinib treatment Median OS for sunitinib (72.7 weeks) expected to be almost twice that of placebo (39.0 weeks; HR, 0.505) based on exploratory analysis of final datab using novel statistical method28 to account for confounding effect on survival of patients crossing over from placebo to unblinded sunitinib

Sunitinib 50 mg/day on Schedule 4/2 recommended for phase II development Clinical benefit rate: 54% (7% PRs, 46% SD 6 months) Median PFS: 7.8 months

Efficacy results

CDD, continuous daily dosing; GIST, gastrointestinal stromal tumor; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PR, partial response; Schedule 4/2, 4 weeks on treatment followed by 2 weeks off treatment in 6 week cycles; SD, stable disease; TTP, time to tumor progression. a Planned interim analysis29. b Final results30.

60

1124

Open-label treatment-use study (offering access to sunitinib to patients for whom it was unavailable prior to regulatory approval in country of origin or who were ineligible to participate in sunitinib clinical trials

Open-label, phase II study assessing sunitinib CDD schedule

Patients randomized 2:1 to sunitinib 50 mg/day (n ¼ 207a/243b) or placebo (n ¼ 105a/118b) on Schedule 4/2

312a 361b

Randomized, double-blind, placebo-controlled, multicenter phase III study

Sunitinib 50 mg/day on Schedule 4/2

Sunitinib at doses of 25, 50, or 75 mg/day on one of three schedules

97

Open-label phase I/II study

Dosing schedule

N

Study design

Table 1. Efficacy of sunitinib in GIST trials.


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G3/4 n (%)


9 (4) 8 (4) 23 (10) 26 (11) 10 (4)

60 (53) 7 (6) 4 (4) 34 (30) 3 (3)

132 (55) 136 (56) 113 (47) 58 (38) 90 (37)

88 (37) 91 (38) 82 (34) 72 (30) 66 (27) 60 (25) 51 (21) 44 (18) 29 (12) 43 (18) 42 (17) 44 (18) 41 (17) 30 (13) 29 (12) 37 (15) 26 (11) 25 (10) 16 (7) 5 (2)

G1/2 n (%)

11 (5) 8 (3) 28 (12) 28 (12) 10 (4)

25 (10) 13 (5) 6 (3) 0 (0) 2 (1) 1 (0.4) 3 (1) 4 (2) 18 (8) 3 (1) 3 (1) 1 (0.4) 3 (1) 13 (5) 13 (5) 0 (0) 6 (2) 3 (1) 2 (1) 0 (0)

G3/4 n (%)

Sunitinibb,d (n ¼ 241)

Double-blind þ open-label phases

Adapted from Demetri et al. (2012)30 with permission. AE, adverse event; EF, ejection fraction; G, grade; LV, left ventricular; NR, not reported. a Per-protocol population. b Four treatment-related deaths were reported during blinded treatment (2%; cardiac arrest, cerebral ischemia, left ventricular failure, and multi-organ failure). c Two treatment-related deaths were reported (2%; cardiac arrest, gastrointestinal hemorrhage). d Four treatment-related deaths were reported during open-label treatment or follow-up (hepatic encephalopathy, hepatic failure, melena, and pneumonia [as coded from the Medical Dictionary for Regulatory Activities]). e Based on the sunitinib arm over the entire study. f Yellow skin was reported in another 125 patients (123 [11%] with G1/2 and 2 [51%] with G3).

124 (54) 126 (55) 105 (46) 85 (37) 87 (38)

2 (2) 0 (0) 0 (0) 2 (2) 0 (0)

G1/2 n (%)

Hematologic laboratory abnormalities Hemoglobin Leukocytes Neutrophils Lymphocytes Platelets

G3/4 n (%)

Placebo (n ¼ 114)

c

2 (2) 0 (0) 2 (2) 0 (0) 1 (1) 0 (0) 1 (1) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 2 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

G1/2 n (%)

Sunitinib (n ¼ 228)

b

Double-blind phasea

Sunitinib Phase III Trial30

Most common (15%) treatment-related non-hematologic AEs or of particular clinical intereste Fatigue 67 (29) 18 (8) 23 (20) Diarrhea 69 (30) 8 (4) 8 (7) Nausea 60 (26) 3 (1) 14 (12) Skin discoloration 62 (27) 0 (0) 5 (4) Anorexia/decreased appetite 46 (20) 0 (0) 5 (4) Dysgeusia 50 (22) 0 (0) 3 (3) Vomiting 38 (17) 1 (0.4) 7 (6) Mucosal inflammation 32 (14) 1 (0.4) 0 (0) Hypertension 18 (8) 9 (4) 4 (4) Rash 34 (15) 2 (1) 6 (5) Stomatitis 35 (15) 1 (0.4) 1 (1) Dyspepsia 33 (14) 1 (0.4) 1 (1) Headache 24 (11) 1 (0.4) 7 (6) Asthenia 25 (11) 6 (3) 2 (2) Hand–foot syndrome 16 (7) 8 (4) 1 (1) Hair color changes 19 (8) 0 (0) 2 (2) Hypothyroidism 6 (3) 1 (0.4) 1 (1) Cardiac disorders 22 (10) 2 (1) 2 (2) Decreased EF 15 (7) 2 (1) 2 (2) LV dysfunction 3 (1) 0 (0) 0 (0)

AE or laboratory abnormality

Table 2. Non-hematologic AEs and hematologic laboratory abnormalities in the sunitinib phase III trial30.




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Across the study, hypothyroidism was reported in 13% and hypertension in 20% of patients. The safety profile observed with long-term treatment in the large treatment-use study (N ¼ 1124; median five treatment cycles started) was very similar to that seen in the phase III study32. Fatigue (42%), diarrhea (40%), and hand–foot syndrome (32%) were the most commonly reported treatment-related non-hematologic AEs, and AEs were mainly grade 1 or 2 in severity. Treatmentrelated hypothyroidism and hypertension were reported in 13% and 26% of patients, respectively. In a retrospective analysis specifically evaluating cardiovascular events in 75 patients enrolled at one center34 in an early phase I/II trial (Table 1)27, cardiovascular events and congestive heart failure (CHF) were reported in 11% and 8% of patients, respectively. Of 36 patients treated with the approved sunitinib dose, a reduction in left ventricular ejection fraction of 15% was noted in 19% and a reduction of 20% in 6%. In final results from the phase III study, the frequency of treatmentrelated cardiac disorders was reported as 11% overall30. In the treatment-use study (N ¼ 1124 at time of analysis), treatment-related AEs related to cardiac function, such as heart failure, CHF, myocardial infarction, and reduced ejection fraction, each occurred with frequencies of less than 0.8%31. Differences in the frequencies of cardiac events found in these studies may have been due, in part, to differences in methodologies used, with higher frequencies reported when more sensitive monitoring procedures were used. A recent blinded and adjudicated retrospective analysis of cardiovascular events in 1090 patients in phase III studies in patients with GIST (versus placebo) or advanced renal cell carcinoma ([RCC] versus interferon alfa) showed hypertension in 47.9% of patients on sunitinib, and symptomatic decreases in ejection fraction in 4.9% of patients35. Both effects were significantly more common with sunitinib than with either placebo or interferon alfa, but incidences of other cardiovascular events (including those possibly related to CHF) were low and did not differ significantly between groups. Notably, the development of hypertension appeared to be predictive of improved overall survival (discussed in more detail below), although there was no such association with ejection fraction. Importantly, 87% of patients with symptomatic ejection fraction reduction were able to continue sunitinib treatment35. The clinical implications of asymptomatic changes in sensitive measures of cardiac physiology remain unclear and are under active investigation.

Safety and tolerability: sunitinib 37.5 mg, CDD schedule In an open-label, phase II study assessing the safety and efficacy of sunitinib CDD (Table 1), the safety profile was 1368


consistent with that reported with intermittent dosing: AEs were mainly grade 1/2 in severity and were manageable through dose modification or standard medical interventions33. The safety profiles on morning and evening dosing, which were also evaluated in the study, were generally similar. Effective drug concentrations were achieved and sustained with CDD, without additional accumulation across cycles.

Sunitinib AEs as potential surrogate biomarkers of efficacy As mentioned above, in a retrospective independently adjudicated analysis of cardiovascular events in patients with RCC or GIST35, hypertension appeared to be predictive of improved overall survival. A link between sunitinib-associated hypertension and improved outcomes (including survival) has also been shown in a retrospective analysis of 544 patients from three studies in metastatic RCC36 and more recently in 319 patients from the phase I/II and phase III GIST studies37. These associations raise the possibility that hypertension may be a surrogate biomarker of sunitinib efficacy, as has been suggested for antiangiogenic agents in general38. It should be noted that blood pressure responses in healthy volunteers appear to be similar to those in patients39. Importantly, clinical and preclinical data indicate that treatment of sunitinib-associated hypertension does not influence antitumor efficacy36,37,40. Several other sunitinib AEs have also been identified as possible biomarkers of sunitinib efficacy. Recent retrospective analyses involving four clinical studies in GIST with a total of 416 patients and five studies in RCC with a total of 770 patients have suggested that sunitinibassociated myelosuppression (neutropenia in GIST and RCC and thrombocytopenia in RCC), hand–foot syndrome, and fatigue correlate with improved clinical outcomes41–45. Similarly, hypothyroidism has been reported to be associated with improved progression-free survival or survival in patients with RCC38.

Sunitinib in the community oncology setting A recent report indicated that treatment patterns with sunitinib (and other angiogenesis inhibitors) differ between community clinics and tertiary centers. In a retrospective review of 250 patients with RCC who received sunitinib or sorafenib at 18 community oncology clinics46, patients were found to be less likely to receive the standard dose of sunitinib or sorafenib than those treated in the tertiary care setting, based on comparison with a similar earlier review of cases from two tertiary centers47. In this recent report, higher rates of treatment modification and shorter treatment durations coupled with lower AE rates www.cmrojournal.com ! 2015 Informa UK Ltd


were also found in community clinics compared with tertiary centers. The author noted the possibility that the high rate of treatment modifications could negatively impact the efficacy of the treatment, as greater exposure to sunitinib has been shown to correlate with greater efficacy48. This underlines the importance of optimizing adverse event management in the community.


Practical implications for practitioners All patients with suspected gastrointestinal sarcomas should be assessed as per National Comprehensive Cancer Network guidelines1. Toxicities should be assessed and monitored throughout the course of a patient’s treatment, and interventions should be offered to mitigate any AEs or symptoms. Early detection and proactive management are key to ensuring that patients remain on therapy. With the intermittent Schedule 4/2 used for sunitinib, outreach to patients between visits may be beneficial in the early weeks of treatment. Psychoemotional support is also needed for patients with metastatic, life-threatening GIST. Focus on oral chemotherapy education and adherence is of utmost importance with many resources now available to practitioners including ASCO and ONS standards for the safe administration and management of oral chemotherapy.

Sunitinib dosing and administration The approved sunitinib dosing schedule is 50 mg/day on Schedule 4/2. Additionally, the results of the CDD study33 suggest that sunitinib 37.5 mg dosed once daily (without a 2 week off-treatment period) offers an alternative dosing strategy that yields broadly comparable efficacy and safety, although the two dosing schedules have not been compared directly in patients with GIST in clinical trials. However, in our experience, sunitinib 37.5 mg on the CDD schedule is reasonably well tolerated, yields fewer tumor ‘flare’ symptoms than Schedule 4/2, and is the sunitinib dosing schedule of choice at our institution. Our clinical observations have recently been supported by data from an ad hoc analysis of the treatment-use study referred to above, which showed that flexible dosing (including CDD administration) may allow patients to stay on treatment for longer periods and achieve better clinical outcomes than strict adherence to Schedule 4/232. The analysis suggested that patients who received flexible dosing remained on treatment longer than those who were managed with strict dosing on Schedule 4/2, and had better clinical outcomes. Furthermore, the overall incidence of AEs was lower when adjusted for duration of treatment. Correct dosing of any anticancer therapy is essential to effective disease management and patient safety, and is ! 2015 Informa UK Ltd www.cmrojournal.com

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therefore a key area for patient education, particularly with oral, self-administered agents such as sunitinib. Patients must be encouraged to be compliant with their prescribed dose and advised not to ‘double up’ if they miss a dose, but to carry on as normal the next day and report the missed dose. Patient diaries can be used to aid compliance. Sunitinib pharmacokinetics Sunitinib has good oral bioavailability with moderate inter-patient variability, and sunitinib bioavailability is unaffected by food49–51. Sunitinib is metabolized predominantly by the cytochrome P450 enzyme, CYP3A422. Consequently, strong inhibitors of the CYP3A4 family may increase sunitinib plasma concentrations, and CYP3A4 inducers may decrease sunitinib plasma concentrations (Table 3)22. Alternative concomitant medications are therefore preferable but, if sunitinib must be co-administered with a strong CYP3A4 inhibitor or inducer, a reduction in the sunitinib dose to a minimum of 37.5 mg/day or an increase to a maximum of 87.5 mg/day, respectively, should be considered22. Exposure–response analysis has shown that GIST patients with the greatest sunitinib exposure experience greater efficacy48, highlighting the importance of maintaining correct dosing. Pregnancy and breastfeeding Sunitinib is in pregnancy category D, and data from animal models suggest potential for human fetal harm22. Table 3. Agents that may affect plasma concentrations of sunitiniba. CYP3A4 inhibitors that may increase sunitinib plasma levels Atazanavir Clarithromycin Grapefruit Indinavir Itraconazole Ketoconazole Nefazodone Nelfinavir Ritonavir Saquinavir Telithromycin Voriconazole CYP3A4 inducers that may reduce sunitinib plasma levels Carbamazepine Dexamethasone Phenobarbital Phenytoin Rifabutin Rifampin Rifapentin St John’s Wortb Based on information in Sutent prescribing information22. a Not a complete list. b St. John’s Wort may decrease sunitinib plasma concentrations unpredictably and should not be taken concomitantly with sunitinib.


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Sunitinib should not be given to women who are pregnant or breast-feeding. Women of child-bearing potential should have a negative pregnancy test before initiating sunitinib treatment. The risk of fetal harm should be explained to all sexually active patients, who should also be counseled about proper contraceptive techniques. Use of two forms of effective contraception is generally recommended.


Managing common sunitinib-related AEs This section outlines common AEs experienced by GIST patients treated with sunitinib (as well as some infrequent AEs of which practitioners should be aware), listed roughly in order of decreasing frequency. Table 422,40,52–68 provides recommended management of the common AEs (listed in alphabetical order) to optimize treatment benefit based on information in the sunitinib prescribing information and published reviews, as well as on my clinical experience gained while developing and participating in clinical trials and managing GIST patients at a specialized center of excellence for cancer care. In addition, a number of meetings of nurses involved in sunitinib clinical trials have been held to discuss and share experiences regarding AE management in patients with GIST and RCC, the results of one of which have been presented previously52. There is less published information on the management of side effects of sunitinib in patients with GIST than with RCC, and some of the recommendations are taken from reviews of dealing with the latter. Pretreatment strategies Good communication between patients and practitioners is essential for optimal management of AEs and should be initiated before treatment commences68. Nurses, in particular, are in a key position to educate patients appropriately and to support their ongoing questions and compliance with therapeutic plans. They can ensure that patients understand their treatment, including potential AEs, and are aware that their nurse is available for advice on AE management. Patients should be informed that dose modifications may be necessary to manage AEs. A thorough baseline assessment for pre-existing risk factors is important and should include identification of concomitant drugs, significant medical history, blood cell counts, blood pressure measurement, and thyroid function tests53,69. Patients should be counseled on potential interactions with other drugs or therapies, including CYP3A4 inhibitors and inducers (Table 2), overthe-counter medications, and alternative/complementary therapies. A patient’s lifestyle should be assessed prior to beginning treatment. Communication among the patient’s entire care team is essential to ensure that sunitinib and concomitant medications are administered safely. 1370


Fatigue Fatigue or asthenia consistently falls among the most frequently reported AEs in both sunitinib GIST and RCC trials: 62% of RCC patients reported fatigue with 15% reporting grade 3 or 4, and 22% of GIST patients reported fatigue or asthenia with 5% grade 3 or 4 (sunitinib prescribing information). Patients should be aware that fatigue may be related to the underlying disease as well as to treatment. Since fatigue is a multifactorial syndrome, potential underlying/contributing causes, such as poor sleep hygiene, depression, hypothyroidism (see below), and anemia need to be investigated and/or ruled out (Table 4)52–54,56. Recommendations for fatigue management should be made by the care teams. In RCC, fatigue/ asthenia appeared to be an uncommon sole reason for dose modification70. There is evidence that the incidence of fatigue/asthenia decreases over cycles in the GIST phase III study (1034) and the expanded-access program70. Fatigue was among the most common treatment-related non-hematologic adverse events in the treatment-use study (42%) and 12% of patients had treatment-related asthenia. Fatigue was also a common reason for dose interruptions and reductions31.

Diarrhea Patients with GIST may have baseline bowel dysfunction related to tumor location, prior surgeries and treatments. Diarrhea accompanying sunitinib treatment is generally Grade 1/2 in severity22, and can usually be managed with standard antidiarrheal medication, adequate hydration, and dietary measures (Table 4)52–55. Patients with continuous, debilitating diarrhea despite concomitant medications and alterations in sunitinib dosing may need to be referred to a gastroenterologist.

Nausea and vomiting Although nausea is one of the more common AEs seen with sunitinib55, the emetogenic potential of sunitinib is low in patients with GIST (fewer than 5% of patients experience grade 3 or 4 vomiting, and 15–25% have grade 1 or 2 vomiting)54. Patients who are affected should be treated with anti-emetics54,55,68, while maintaining hydration (Table 4)54.

Anorexia Anorexia is commonly associated with one or more underlying gastrointestinal AEs, including diarrhea, nausea, taste disturbance52,54, mucositis54,55, and stomatitis54,55. Anorexia rarely requires dose reductions or dosing interruptions and is generally managed by focusing on underlying causes, which should be investigated if the patient loses more than 5 pounds in weight. www.cmrojournal.com ! 2015 Informa UK Ltd

Dosing interruption/delay for grade 3/4 AE, consider dose reduction for grade 4 AE53,54

Infrequent/rare (only at patients’ specific request)53

Treatment interruption and dose reduction for grade 3 AE55 (dose reduction rare; sometimes implemented after patients have received one additional cycle53); treatment should be interrupted until symptoms resolve to grade 1; dose reduction may then be considered55

Days 2–5

Days 14–2156,57

Typically after 2–4 weeks54,55, usually after repeated treatment55

Diarrhea

Fatigue

Hand–foot syndrome

None generally required (unless in combination with another AE)52–54

Day 14 (variable)

Anorexia

Sunitinib dose modification

Onset/observed

AE

Management Additional management approaches



(continued )

Examine hands and feet and assess for predisposing factors58; recommend manicure and pedicure and refer to a podiatrist before starting therapy54,55; remove pre-existing calluses and keratotic skin59 Educate patients on the time course and nature of symptoms55,58 Advise patients to decrease pressure on affected areas, to stay off their feet whenever possible, and to avoid friction or pressure on the hands/ feet54 through avoidance of: – tight-fitting shoes – tight-fitting jewelry – heavy activity To prevent pressure/friction advise: – loose-fitting clothes54 – use of orthotic devices55,58 – use of cosmetic gloves52,59 or booties where appropriate59 Advise avoidance of extreme temperatures52; wash with lukewarm rather than hot water and gently pat dry54 Advise frequent use of emollient creams and ointments52 (e.g., Bag Balm, Dairy Assoc. Co. Inc., Lyndonville, VT; creams containing keratolytics55, lanolin or urea54,55,58,59); use pain medication54,55 In erythematous areas, recommend use of steroidal preparations (clobetasol propionate 0.5%)59; pyridoxine and systemic corticosteroids may also be tried60

Pretreatment counseling on fatigue associated with disease and treatment52,54–56 Laboratory and clinical evaluations to rule out underlying causes of fatigue (e.g., depression, anemia, hypothyroidism)52–54,56 – Manage any underlying cause with standard medical procedures Advise changing the time of administration of dose

Standard antidiarrheal medication52–53 (begin with loperamide, adding diphenoxylate–atropine and then deodorized tincture of opium for severe symptoms) Advise patients to take extra fluids while experiencing diarrhea to avoid dehydration; discontinue stool softeners and fiber supplements52,54 Discuss dietary changes and refer to a nutritionist if necessary52–54

Investigate possible underlying causes (e.g., mucositis and dysgeusia)50,54,55 Consult with a dietician and provide patient education50,54,56 Advise patients to: – avoid foods that cause other AEs (e.g., diarrhea) – eat several small meals throughout the day rather than three full meals

Table 4. Selected common AEs experienced by patients with GIST treated with sunitinib: timing of onset and recommended management.



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Advise patients53: – of the potential for these AEs, to prevent anxiety – that these AEs are generally reversible on treatment discontinuation

None generally required; consider dose reduction or switching to 37.5 mg on CDD schedule if unresponsive to supportive measures55

Dosing interruption/delay or dose reduction for grade 3 AE53

None52

Variable

Days 7–14 (variable)57

Nausea and vomiting

Oral changes (e.g., pain, glossodynia, taste disturbance, cheilitis, stomatitis ulcerations)

Advise dietary changes: eat and drink often in small amounts67 Suggest taking sunitinib at night55 Treat with anti-emetics54,55,68 Maintaining hydration is extremely important67 – evaluate patients experiencing continuous episodes of vomiting to assess the need for intravenous hydration

Assess thyroid function at baseline22,54,55 Monitor during sunitinib treatment and if signs or symptoms of hypothyroidism are observed22,55,66 Treat with thyroid hormone replacement therapy as appropriate55,65,66; treatment should also be considered for patients with subclinical hypothyroidism54,66

Assess baseline blood pressure62 (preferably two separate sessions63) and treat pre-existing hypertension; assess renal status62,64 Encourage lifestyle modification64 Measure blood pressure frequently during treatment22,62 (most frequently during first treatment cycle)63,64 Maintain regular contact with hypertensive patients to ensure compliance with antihypertensives Standard antihypertensive therapy22,40,62–64; avoid drugs known to interact with CYP3A4 (some CCBs)40,55,64 and use care with drugs that prolong the PR interval (b-blockers and CCBs)54

Recommendations are based on personal experience if not otherwise referenced. AE, adverse event; CCB, calcium channel blocker; CDD, continuous daily dosing; G-CSF, granulocyte colony stimulating factor; GIST, gastrointestinal stromal tumor.

Skin discoloration typically week 1; hair depigmentation weeks 5–6; hair loss weeks 3–15 (variable)59

None generally required54,55,65,66

Variable65,66

Hypothyroidism

Skin/hair issues (e.g., hair/skin discoloration, hair thinning)

Non-alcoholic, anesthetic mouthwash to provide temporary relief of symptoms of mucositis/stomatitis52,54,55 Mild, non-peroxide toothpastes to help lessen oral discomfort52,54 Topical products such as lip creams/balms for cheilitis52,54 (e.g., Aquaphor [Eucerin], Beiersdorf AG, Wilton, CT) Advise making dietary modifications52,54,55, such as avoiding: – spicy or acidic foods – alcohol – foods at high or low temperatures

Dosing interruption for severe hypertension22,54,55,62

Perform complete blood counts before each cycle53,54 Non-febrile neutropenia and thrombocytopenia: standard neutropenic and thrombocytopenic precautions54 – In cases of repeated, severe neutropenia, use of G-CSF may be considered55 Anemia: – symptomatic anemia: standard therapy54,55

Variable

Dosing interruption/delay if grade 3 AE persists after 2 week off-treatment period53,54 Treatment interruption for grade 4 AE61 Recurrent neutropenia or thrombocytopenia persisting after 5 days: dose reduction on the next cycle54,61

Hypertension

Additional management approaches

Typically noted at first follow-up assessment on day 28

Management

Hematologic abnormalities (anemia, neutropenia, thrombocytopenia)

Sunitinib dose modification

Onset/observed

AE

Table 4. Continued.






Patients should be given dietary and lifestyle advice (Table 4) to help manage symptoms. Oral changes Oral changes include dysgeusia, mucositis, increased sensitivity, pain, and inflammation22,53–55. Patients may experience mouth pain without obvious changes in the mucosa. Oral toxicity reported in association with multitargeted tyrosine kinase therapy is characterized by dysesthesia with lack of clinical signs71. Symptoms can be very distressing for patients and should be managed promptly (Table 4). Patients should be educated and counseled on the possibility of experiencing these symptoms and their management. Skin discoloration and hair depigmentation Skin discoloration on sunitinib therapy commonly involves yellowing of white skin, probably due to the yellow color of the drug, and depigmentation of dark skin due to inhibition of KIT22,50,59. The yellowing of skin is not due to jaundice. Skin discoloration can be disturbing for patients, who should be warned of this possible AE before starting sunitinib, in order to decrease potential anxiety (Table 4). Hair depigmentation is seen as well22, also likely due to KIT inhibition59. Patients have exhibited ‘zebra-like’ hair, growing whitish-gray in color while on sunitinib treatment and returning to its normal color during the 2 weeks off treatment in each cycle50,59. Patients should be reassured that the change in hair and/or skin color is generally reversible when treatment is discontinued. Hypertension and cardiac dysfunction Patients should be assessed for hypertension (Table 4) and cardiac function before and during treatment, and treated as needed with standard medical management22,40,62–64. Blood pressure should be measured using the same device if possible, as there is considerable variation between equipment. Given that most antiangiogenic drug regimens include periods off of the agent, close monitoring during those periods is required, because rebound hypotension may also occur72. Practitioners should be in regular contact with patients experiencing these AEs to ensure compliance. Several sets of recommendations for the monitoring and treatment of hypertension associated with VEGF signaling pathway inhibitors have been published in recent years62–64. The sunitinib prescribing information recommends that patients with concurrent cardiac conditions should be carefully monitored for any signs and symptoms of CHF as they are at a higher risk of developing left ventricular dysfunction22. Sunitinib should be discontinued in patients with clinical symptoms of CHF. ! 2015 Informa UK Ltd www.cmrojournal.com

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Clinical experience suggests that most affected patients show significant improvements in symptoms and cardiac function within 4 weeks of drug discontinuation and appropriate treatment, although the long-term consequences of cardiovascular dysfunction associated with targeted therapy remain unclear73. Hand–foot syndrome (HFS) HFS tends to be related to dosing54,55 and often decreases or subsides during the 2 week off-treatment periods55,58. Symptoms include sensitive, painful hands and/or feet, with dry blisters and/or dry cracking skin and calluses that often appear related to constant pressure placed on hands and/or feet. HFS due to kinase inhibitors such as sunitinib presents differently from that reported with cytotoxic chemotherapy. HFS with kinase inhibitors is generally localized to areas of friction or trauma, such as over the joints and tips of the finger and toes, or the heels. In addition, blisters and calluses are surrounded by a halo of erythema58,74. In contrast, HFS with conventional cytotoxic chemotherapy presents as symmetrical paresthesias, erythema, and edema in the palms and soles, which may develop into blistering desquamation and necrosis, followed by ulceration and crusting55,58,60. However, HFS with sunitinib can occur anywhere on the body, so practitioners should conduct full body assessments. In particular, a clinical examination of the hands and feet should be carried out, and predisposing factors identified before starting therapy58. HFS can be very distressing for patients59, and practitioners should offer advice to patients on symptom relief and preventative measures (Table 4). Hypothyroidism Hypothyroidism is recognized as a potential risk of long-term sunitinib treatment, and monitoring for thyroid function before and during treatment is recommended22,54,55. Thyroid panel should be measured at baseline and day 1 of each cycle through cycle 4. After cycle 4, thyroid panel should be assessed every 3 months or as clinically indicated70. Hypothyroidism can be managed using thyroid hormone replacement therapy without the need for treatment discontinuation or interruption (Table 4). Algorithms for the management of thyroid dysfunction and hypothyroidism have been proposed for patients receiving TKIs65,66. Patients should be informed that symptoms of hypothyroidism include fatigue, intolerance to cold, hair thinning, and constipation. Hematologic abnormalities Patients with metastatic or unresectable GIST are prone to occult bleeding or may have undergone gastrectomy or Sunitinib treatment management in GIST Pilotte

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bowel surgery and thus be at risk of vitamin B12 or folate deficiency55. Additionally, prior long-term imatinib treatment may result in mild anemia55. It is therefore important to monitor blood counts to identify anemia. Anemia can be managed per local guidelines. In severe cases, dose modification may be required (Table 4)61. Patients may experience decreased absolute neutrophil counts and decreased platelet counts. These changes are generally reversible and tend to resolve during off-treatment periods, but may recur54,55. Patients with sunitinib-induced neutropenia rarely experience febrile neutropenia. They can be managed through dose modification (Table 4).

knowledge, and education, patients with GIST can be safely cared for, with the goal of providing effective therapy and optimal symptom control.

Hepatotoxicity Hepatotoxicity, possibly resulting in liver failure or death, is a boxed warning in the sunitinib prescribing information, based on seven cases observed in clinical trials involving 2281 patients (0.3%) and post-marketing experience22. Monitoring of liver function tests (alanine aminotransferase, aspartate aminotransferase, and bilirubin) is therefore recommended before the start of treatment, during each treatment cycle, and as clinically indicated. Sunitinib dosing should be interrupted for grade 3 or 4 treatment-related hepatic AEs and discontinued if there is no resolution22.

Declaration of financial/other relationships A.P.P. has disclosed that she has participated in advisory boards for Pfizer, Ariad, and Bayer. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Conclusion Clinical outcomes for patients with GIST at all stages have improved markedly since the development of therapy targeting the root cause of this disease via inhibition of uncontrolled kinases. Sunitinib is considered the standard of care for patients with advanced, unresectable GIST following failure of imatinib due to disease progression or intolerance and provides significant clinical benefit to this patient population for whom effective therapies were not previously available. Although sunitinib therapy is associated with a range of AEs, the majority can be managed with standard medical interventions or dose modification. An important objective for further research is to characterize possible differences between GIST and RCC patients in the safety of sunitinib. Generally speaking, the safety profiles are similar for the two indications, with the exception of certain notable side effects in GIST patients such as tumor ‘flare’. Recent data linking several AEs with improved clinical outcomes with sunitinib, while requiring validation in larger controlled studies, highlight the need to manage AEs effectively. This may be particularly true in the community clinic setting, where a tendency toward attenuation of treatment in the face of AE development has been observed. Through communication, support, 1374


Transparency Declaration of funding Editorial assistance for this study was funded by Pfizer. The manuscript was written, the content was controlled, and the decision to submit the paper for publication was made solely by the author, who received no financial support or other compensation related to the development of this paper. Pfizer Inc., the manufacturer of sunitinib and the sponsor of many of the studies described in this manuscript, reviewed the paper for scientific accuracy.

Acknowledgments The author acknowledges Dr. George D. Demetri (Dana-Farber Cancer Institute, Boston, MA, USA) for his guidance and support in the development of this manuscript. In particular, I thank Joanne Ryan PhD RN of Pfizer for critical review of the manuscript. Editorial assistance was provided by Cherry Bwalya and Wendy Sacks at Acumed (Tytherington, UK and New York, NY, USA) and was funded by Pfizer Inc.

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