Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal tumor:...

REVIEW ARTICLE

Sunitinib malate in the treatment of renal cell carcinomaand gastrointestinal stromal tumor: Recommendations forpatient management*

Jayesh DESAI,1,2 Howard GURNEY,3 Nick PAVLAKIS,4 Grant A McARTHUR2,5 andIan D DAVIS6

1Royal Melbourne Hospital, 5Department of Medicine, St. Vincent’s Hospital, University of Melbourne, Parkville, 2PeterMacCallum Cancer Centre, St Andrews Place, East Melbourne, 6Ludwig Institute Oncology Unit, Austin Health, Heidelberg,Victoria, 3Westmead Hospital, Westmead, and 4Royal North Shore Hospital, St Leonards, New South Wales, Australia

Abstract

Sunitinib malate (SU011248, Sutent® [Pfizer]) is an oral multitargeted tyrosine kinase inhibitor with efficacyagainst renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Sunitinib has been approvedby various regulatory authorities for treatment of advanced RCC and unresectable and/or malignant GISTfollowing failure of imatinib mesylate treatment due to resistance or intolerance. Sunitinib is generally welltolerated, with most side-effects being mild to moderate. The most common adverse events are lethargy,diarrhea, stomatitis, hand–foot syndrome and hypertension. Uncommon but important adverse effects arehypothyroidism and hematological toxicity (neutropenia and thrombocytopenia), which require monitoring.Caution is recommended when using concurrent inhibitors or inducers of CYP3A4. The frequency andseverity of side-effects often correlates with increased drug exposure. In clinical trials, side-effects seldom ledto treatment discontinuation. This paper summarizes the published literature and provides recommenda-tions for patient assessments and management of treatment-related side-effects.

Key words: gastrointestinal stromal tumor (GIST), multitargeted tyrosine kinase inhibitor (TKI), renal cellcarcinoma (RCC), sunitinib.

INTRODUCTION

Receptor tyrosine kinases (RTK) regulate cell growth,differentiation and angiogenesis. Aberrant activation ofRTK is frequently implicated in the biology of varioushuman cancers and pathologic angiogenesis. Many ofthe processes involved in tumor growth and progres-sion are blocked by inhibition of RTK. Sunitinibmalate (SU011248, Sutent® [Pfizer]) is an oral ATP-competitive tyrosine kinase inhibitor (TKI) that hasdirect antitumor activity and also has antiangiogenicactivity. Sunitinib targets vascular endothelial growthfactor receptors (VEGFR) types 1, 2 and 3 and platelet-derived growth factor receptors (PDGFR), which havean essential role in transduction of extracellular signalsand angiogenesis induction. Sunitinib also inhibits stemcell factor receptor (KIT), FMS-like tyrosine kinase-3receptor (FLT3) and the glial cell-line derived neuro-trophic factor receptor (RET). These receptors are

Correspondence: Dr Jayesh Desai, Department of MedicalOncology, Royal Melbourne Hospital, Parkville, Vic. 3050,Australia. Email: [email protected]

*The authors are all members of the Australian Pfizer SutentAdvisory Board. Jayesh Desai is also member of the NovartisGIST Advisory Board, and has received speaking honorariafrom Pfizer and Novartis. Howard Gurney is chair of WyethTorisel (RCC) Advisory Board and a member of the BayerNexavar Advisory Board. Nick Pavlakis has receivedspeaking honoraria from Pfizer and Bayer. Grant AMcArthur is a member of the Novartis GIST AdvisoryBoard. Ian D Davis is also chair of the Bayer NexavarAdvisory Board and a member of the Wyeth Torisel (RCC)Advisory Board, with all payments for his work donated tothe Austin Hospital Medical Research Foundation to supportresearch into urologic cancers. The information in this paperwas collected, analyzed and interpreted by the authors. Pfizerwas not involved in the preparation of the paper, but had theopportunity to review and approve the paper before it wassubmitted.

Accepted for publication 15 October 2007.

Asia–Pacific Journal of Clinical Oncology 2007; 3: 167–176 doi:10.1111/j.1743-7563.2007.00136.x

© 2007 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

mailto:[email protected]

important in signal transduction and growth of anumber of solid tumors.1,2

Clinical studies have shown that sunitinib has activityagainst gastrointestinal stromal tumor (GIST) and meta-static renal cell carcinoma (RCC).3,4 Sunitinib also hasanticancer activity in patients with metastatic breastcancer,2 colon cancer,2 neuroendocrine cancer,5 advancedurothelial cancer,6 unresectable hepatocellular carci-noma,7 and recurrent advanced non-small cell lungcancer.8

Approvals, indications and

recommendations

Sunitinib received accelerated approval from the USFood and Drug Administration (FDA) in January 2006for the treatment of advanced RCC and approval forGIST after disease progression or intolerance to imatinibmesylate therapy.3,4

The Australian Drug Evaluation Committee (ADEC)in August 2006 also recommended that sunitinib beapproved for registration for GIST after failure ofimatinib treatment and for the treatment of advancedRCC.9

In January 2007, the European Commission grantedfull approval for sunitinib treatment of advancedand/or metastatic RCC and treatment of unresectableand/or metastatic malignant GIST after failure ofimatinib therapy due to resistance or intolerance.10 TheEuropean Association of Urology (EAU) guidelines rec-ommend sunitinib as first-line therapy in patients withadvanced and/or metastatic RCC of good and inter-mediate risk.11

Sunitinib in the treatment of GIST

GIST are the most common mesenchymal tumors of thegastrointestinal tract and are highly resistant to conven-tional chemotherapy and radiotherapy. GIST usuallyhave activating mutations in the RTK genes KIT orPDGFRA, leading to uncontrolled cell proliferation andresistance to apoptosis.12 Most patients treated with theRTK inhibitor imatinib respond to treatment, with theduration of response correlating strongly with the site ofprimary mutations in KIT. The most durable responsesto imatinib are seen in GIST with mutations in exon 11of KIT, while patients whose GIST have mutations inexon 9 or those without detectable KIT/PDGF muta-tions have a significantly shorter duration of response.Resistance to imatinib is; however, emerging as aproblem. The most common mechanism for this is dueto selection of secondary KIT mutations in the kinase

domain, preventing imatinib binding to KIT. Themechanisms underlying resistance in exon 9 mutationsare less well understood, and may relate to alterationsin KIT receptor activation.12 Early data suggest thatpatients with GIST with KIT exon 9 mutation maybenefit more from sunitinib than those with exon 11mutation, although the majority of patients with exon11 mutations in this study had secondary kinase domainmutations.13

The FDA approval of sunitinib for single agent treat-ment of GIST was based on the results of a double-blindclinical trial that included 312 adults with GIST,randomized 2 : 1 to either oral sunitinib (50 mg) orplacebo once daily for 4 weeks followed by 2 weeks offmedication. Sunitinib significantly increased mediantime to tumor progression, to 27.3 weeks comparedto 6.4 weeks for placebo (P < 0.0001). Sunitinib alsoresulted in superior progression free survival(24.1 weeks, vs. 6.0 weeks; P < 0.0001). The objectiveresponse rate for sunitinib treated patients was 6.8% vs.0% for those on placebo (P = 0.006).14

Sunitinib in the treatment of RCC

Clear cell RCC accounts for 85% of all RCC. Thepathogenesis and progression of clear cell RCC isthought to be substantially dependent on the loss offunction of the tumor suppressor gene, von Hippel-Lindau (VHL). This leads to an increase of hypoxia-inducible factor, with overexpression of the pro-angiogenic factors VEGF and PDGF. Until recently,the most active agents in the treatment of metastaticRCC were the cytokines interferon-alpha (IFN–a) andinterleukin-2 (IL-2), however, both cytokines offerlimited benefit,15,16 and cause severe toxicity in the caseof IL-2.17

FDA approval of sunitinib as a single-agent for thetreatment of RCC was based on two single-arm phase IImulticentre studies (n = 63 and 106) of sunitinib inpatients with metastatic, cytokine-refractory RCC.Partial responses were observed in 25.5% of patients inone study and 36.5% of patients in the second study.Median response durations in the two trials were27.1 weeks and 54 weeks.3,4

An international phase III trial of sunitinib versusIFN-a in the first line treatment of metastatic RCCdemonstrated that sunitinib led to significant improve-ment in progression free survival and objective responserate. Previously untreated patients (n = 750) with clearcell metastatic RCC, good prognosis and performancestatus (ECOG 0 or 1) were randomized to receive either6-week cycles of sunitinib (50 mg once daily for

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Asia–Pac J Clin Oncol 2007; 3: 167–176

4 weeks, followed by 2 weeks without treatment) orIFN-a2a (9 mol/LU three times weekly). Sunitinib wasassociated with a higher objective response rate thanIFN-a (31% vs. 6%, P < 0.001).16 Use of sunitinib morethan doubled progression-free survival (PFS) comparedwith IFN-a (11 vs. 5 months, P < 0.001). A multivariateanalysis of baseline features that predicted shorter PFSfor the sunitinib group included time since diagnosis ofless than 1 year, ECOG performance status >0, andhypercalcemia.18

Tolerability of sunitinib

Sunitinib is generally well tolerated, with a spectrum ofside-effects seen with other similarly targeted kinaseinhibitors but different to that of conventional cytotoxicchemotherapy. Side-effects related to sunitinib in clinicaltrials for the treatment of metastatic RCC and GISTwere generally mild or moderate, and usually manage-able with additional supportive measures, dose reduc-tion or dose interruption. Discontinuation of treatmentwas seldom necessary. It is important to note that thecumulative incidence of side-effects in sunitinib-treatedpatients will inevitably be higher than placebo or controlcomparator arms, since patients will remain on treat-ment for longer periods.

Most adverse events were NCI CTCAE grade 1 or 2in severity (mild or moderate). Overall, treatment-related adverse events for sunitinib versus placebowere seen in 83% versus 59% of GIST patients, withthose considered serious occurring in 20% versus 5%,respectively. Side-effects more common with sunitinibincluded diarrhea, mucositis, hypertension and skinabnormalities (skin discoloration and hand–foot syn-drome). Elevated liver enzymes and myelosuppressionwere more common with sunitinib than with placebobut were seldom of clinical significance. Acquiredhypothyroidism was described in 4% of patients receiv-ing sunitinib and 1% of those receiving placebo in thistrial,3,4,14 however, this may be an underestimate.19,20

Dose reductions were required for 11% of sunitinib and0% of placebo patients. Importantly, symptoms suchas fatigue, which have been reported at high rates insingle-arm phase trials, were essentially the same inboth groups, suggesting that the advanced diseasestatus of these patients contributes significantly to thissymptom.14

Similarly, adverse events in clinical trials of sunitinibin metastatic RCC were predominantly mild to moder-ate. In the first-line Phase III trial of sunitinib versusIFN-a, higher rates of grade 3 diarrhea, vomiting, hyper-tension and hand–foot syndrome were seen with suni-

tinib, however, patients in the sunitinib group reported asignificantly better quality of life than did patients in theIFN-a group (P < 0.001).16 Additionally, fewer patientsdiscontinued sunitinib because of treatment-relatedadverse events. The most common serious (grade 3 or 4)treatment-emergent adverse events for sunitinib andIFN-a are summarized in Table 1.

Management recommendations

Sunitinib is a highly active drug in RCC and GIST andpatients benefit most if they can be kept on treatment.As a general principle, mild to moderate toxicitiesshould be managed with supportive measures and con-tinuation of sunitinib dosing, where possible. Severetoxicities should be managed by interruption in suni-tinib dosing until recovery to a mild/normal level,followed by recommencement at a reduced dose.Importantly, most toxicities improve during the 2-weekrest period (on the recommended 4-week on/2-week ofdosing schedule), so this should be taken into consider-ation if dose adjustments are planned. Outlined inTable 2 are suggested assessments for patients treatedwith sunitinib.

It is strongly recommended that the management ofpatients receiving sunitinib be centralized through amultidisciplinary group including clinicians experiencedin the recognition and treatment of toxicity related tosunitinib. It is also important to recognize that patientswith advanced cancer have needs other than thoserelated to the prescription of an oral drug, and requireappropriate multidisciplinary expertise in their care.

The following practice recommendations are based onliterature review and author personal experience withthe use of sunitinib in Australia. They are not intendedto supplant approved product information and educa-tion of patients.

Gastrointestinal side-effects

Diarrhea, nausea and vomiting are common side-effectsof sunitinib treatment. All are generally easily managedand reversible by the use of appropriate concomitantmedications. Supportive measures such as eating smallfrequent meals and drinking regular but small volumesof fluid to prevent dehydration are important. Reduc-tion of dose or interruption of treatment is usually notrequired but should be considered for patients experi-encing greater toxicity or where symptomatic measureshave not been effective.14,16 Early recognition and imple-mentation of appropriate therapy is key to maintainingpatients on treatment.

Sunitinib: patient management recommendations 169



Mucositis and stomatitis are frequently reported andmay manifest as overt ulcers or as a report of mouthpain, loss of taste, or difficulty in swallowing or speech.Clinicians need to be aware that these symptoms canalso occur without clear evidence of physical signs.Mucositis/stomatitis is mild in most cases and usuallydoes not require dose modification. Mucositis is treatedsymptomatically with mouth washes, analgesia and sup-portive measures such as nutritional advice from a dieti-tian. In more severe cases (affecting swallowing and oralintake) dose interruption and reduction of dose for sub-sequent cycles may be required.

Effects on thyroid function

The incidence of hypothyroidism may be higher thaninitially reported and increases with the duration ofsunitinib therapy, although it is not clear whether theincidence is related to daily sunitinib dose. In the GISTpopulation (after treatment with imatinib), the inci-dence was 18%, 29% and 90% after 36, 52 and96 weeks of treatment, respectively. Abnormal serumthyroid stimulating hormone (TSH) values have beendocumented in 62% of GIST patients receiving suni-tinib.19 Sunitinib caused hypothyroidism in 36% ofpatients, with 20% of patients having clinically signifi-cant thyroid impairment. Similar results have beenreported in patients with RCC, with 85% of patientsdeveloping abnormal thyroid function; 84% of these

patients developed signs or symptoms of abnormalthyroid dysfunction.20 Hyperthyroidism may also occurbut is probably less common.19 It is not usually associ-ated with clinical manifestations and resolves sponta-neously in most patients without the need for treatmentor modification of sunitinib dose. Many of thesepatients will go on to become hypothyroid so thyroidsuppressive treatment is usually not required. However,some patients may experience symptomatic thyrotoxi-cosis or thyroid storm requiring interruption of suni-tinib dosing, as early as during the first cycle oftreatment. Clinicians should have a low threshold ofsuspicion for diagnosis of these conditions and suchpatients should be managed in conjunction with anendocrinologist. The development of sunitinib-inducedthyrotoxicosis does not preclude the future treatmentof that patient with sunitinib.

Given the high frequency of thyroid dysfunction, andthe non-specific nature of its associated symptoms, allpatients treated with sunitinib should be screened for thedevelopment of hypothyroidism with TSH measure-ments taken prior to commencement of treatment, andat the end of the dosing period of each cycle of treat-ment.19,20 Abnormal serum TSH values should promptmore thorough investigation and consultation with anendocrinologist. It is also important to recognize thatalthough constitutional symptoms such as fatigue arecommon manifestations of advanced cancer and a

Table 1 Most common grade 3 or 4 adverse effects reported in controlled trials of sunitinib in advanced RCC or imatinib-resistantGIST

Side-effect Frequency % (sunitinib)† Frequency % (placebo)‡ Frequency % (IFN)§

Abdominal pain 11–33 12–38 NRAsthenia 4–22 3–11 4–20Altered taste 21 12 NRAnorexia 33 29 NRBleeding (all sites) 7–18 9–17 NRChanges in hair color 14 NR 1Diarrhea 4–53 0–27 0–12Dry skin 16 NR 5Fatigue 7–51 8–47 12–51Fever 18 17 NRHand–foot syndrome 4–20 3 1Hypertension 4–24 0 1Mucositis/stomatitis 25–29 18 2Nausea 31–44 32 33Rash 19 NR 6Skin discoloration 16–30 23 NRVomiting 4–24 24 1–10†Both GIST and RCC trials. ‡GIST trials only.

§RCC trials only. NR, not reported.

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recognized toxicity of sunitinib, they can also representearly features of thyroid dysfunction and so need to beinvestigated accordingly.

Patients who develop hypothyroidism (manifested asan elevated TSH) should be treated with thyroid replace-ment therapy. Thyroid hormone replacement therapymay also be effective in symptom relief. Patients withhypothyroidism readily respond to thyroid replace-ment therapy and dose modification of sunitinib is notrequired.19,20

Hemorrhagic side-effects

Sunitinib, because of it antiangiogenic effects, may com-promise wound healing and predispose to a bleedingtendency. In the sunitinib phase III study, gastrointesti-nal (GI) or intratumoral bleeding was reported in 3% ofGIST patients. GI perforation has occurred rarely inpatients taking sunitinib.21 Patients should be closelymonitored for signs and symptoms of GI perforationor intratumoral bleeding. In the phase III GIST study,general hemorrhagic events were noted in 18% ofpatients on sunitinib and 17% on placebo. Epistaxisaccounted for the majority of these effects, was self-limiting, and did not require drug modification.14 In thepivotal phase III trial in RCC, the incidence of epistaxisin patients on sunitinib was 12%. Sunitinib is contrain-dicated in patients on therapeutic doses of warfarin. Ifanticoagulation is required during sunitinib therapy,consideration should be given to whether the patientshould continue sunitinib. If so, a low molecular weightheparin is the anticoagulant of choice.

Hypertension

All agents that inhibit VEGF are associated with hyper-tension, which can be severe. With sunitinib, hyperten-sion was reported in 15–28% of patients in the pivotalphase III GIST and RCC trials. It was severe andrequired treatment (�Grade 3) in 4–8%. Hypertensionrequiring treatment has been defined as a 20 mmHgrise in systolic or diastolic pressure above baseline ORany sustained blood pressure >150/90 mmHg. Regularmonitoring of blood pressure is recommended duringsunitinib treatment and it is recommended that patientsmonitor their blood pressure at home. If hypertensionoccurs it should be actively treated with standard anti-hypertensive medication with the aim of normalization.Although there is no clear consensus as to which anti-hypertensive agent should be used first, ACE inhibitorsor calcium-channel blockers (dihydropyridine calciumchannel blockers only) have been shown to be effectivein controlling VEGF-induced hypertension.22 Care again

Table 2 Minimum recommended safety assessments for treat-ment with sunitinib

Cycle number/dayof cycle Recommended safety assessments

Baseline • Baseline symptom history, ECOGperformance status

• Bloods: Full blood examination,renal and liver function, thyroidfunction (TSH/fT4/fT3)†

• Blood pressureC1/D14 • Symptom/Toxicity history

• Blood pressure• Other investigations as warranted,

e.g. thyroid function if concernsabout early hyperthyroidism

C1/D28 • Symptom/Toxicity history, ECOGperformance status

• Blood pressure• Bloods: Full blood examination,

renal and liver function, thyroidfunction (if TFT were normal atbaseline, only TSH needs to bedone)



renal and liver function, thyroidfunction (if prior TFT were normal,only TSH needs to be done)



renal and liver function, thyroidfunction (if prior TFT were normal,only TSH needs to be done)

Subsequentcycles

• Patients should be seen (at aminimum) once every cycle.

• If patients are only seen on day 1,review toxicities from prior cycles;blood pressure must also bemonitored (with home monitoringor by patient’s general practitioner)during the on-treatment period.

• Bloods: Full blood examination,renal and liver function, thyroidfunction (if prior TFT were normal,only TSH needs to be done)

†If abnormal thyroid function, patient should be referred to anendocrinologist.




needs to be taken to avoid drug–drug interactionsbetween these agents and sunitinib (see Table 4). Insevere cases temporary suspension of sunitinib is recom-mended until hypertension is controlled.21

Cardiac effects

Sunitinib should be used with caution in patients withuncontrolled ischemic heart disease due to its antiangio-genic effects. Patients with a history of cardiac eventsmay have an increased risk of developing left ventriculardysfunction when taking sunitinib. They should bemonitored for clinical signs and symptoms of congestiveheart failure (CHF) and baseline and periodic evalua-tions of LVEF should be considered, particularly forpatients with other risk factors for CHF.21 If CHFoccurs, sunitinib should be discontinued. In patientswithout clinical evidence of CHF but with an ejectionfraction below 50%, or with a greater than 10% drop inLVEF from baseline, treatment should be interruptedand/or the dose should be reduced.21

Sunitinib has a dose-dependent effect on QT intervalprolongation, with an associated risk of ventriculararrhythmias, and should be used with caution inpatients with a history of QT interval prolongation, orwho are taking antiarrhythmics, or who have preexist-ing cardiac disease, bradycardia, or electrolyte abnor-malities. Periodic ECG and monitoring of magnesiumand potassium should also be performed in thesepatients.21

Dermatological effects

Apart from hand-foot skin reaction, which is detailedbelow, skin toxicity from sunitinib is usually mild. Skindryness is common and usually mild, and is managedwith simple supportive measures such as emollients.Sunitinib capsules are formulated as a yellow powder,which can lead to yellowing of the skin in approximately30% of patients. It is important to educate both patientsand clinicians that this is not jaundice, however, liverdysfunction may need to be excluded.

Changes in hair color with graying of hair, eyebrowsand eyelashes, are very common with sunitinib therapy.Apart from the cosmetic issues, this is not a significanteffect and does not require dose modification.

Hand–foot syndrome (palmar-plantar

erythrodysesthesia)

Hand-foot skin reaction (HFS) occurs in approximately15–20% of patents taking sunitinib and is the mostcommon reason for dose alterations.14,16 Although this

may appear as early as the first cycle, toxicity is mostcommonly cumulative after repeated cycles of treat-ment. Symptoms typically appear after 2–4 weeks oftreatment and present as painful erythematous areas onthe palms and soles. Painful hyperkeratotic lesions anddesquamation may follow, typically in areas exposed topressure or friction. Patient education, early recogni-tion of symptoms and aggressive management areessential, as symptoms can be severe and significantlylimit function and quality of life. Emollient and kera-tolytic ointments (containing salicylic acid or urea) canbe used to decrease keratosis. Simple preventative mea-sures should be encouraged, such as pressure-absorbinginsoles and comfortable shoes or gloves when perform-ing activities such as gardening. Referral to a podiatristcan be very helpful and should be recommended. Edu-cating patients about the time course of symptoms isimportant, as HFS improves rapidly during the 2-weekwashout period at the end of each cycle of treatment.HFS does appear to be dose-dependent so grade 3 HFScan be managed by treatment interruption until symp-toms resolve to grade 1, followed by dose reduction.Analgesia for pain control may be needed until symp-toms improve.23

Myelosuppression

Hematological effects are seen commonly with suni-tinib, and although these effects are rarely of clinicalsignificance, they need to be specifically monitored forand managed accordingly. Mild neutropenia (grade 1or 2) was seen in 53%, moderate (grade 3) effects in8% and severe (grade 4) in 2% of patients in the GISTphase III trial.14 In the 1st-line RCC study, respectiverates of toxicity were 72%, 11% and 1%.16 Febrileneutropenia was rare (1%) in both patient popula-tions. Thrombocytopenia is mild in most cases (33%in GIST, 65% in RCC), with grade 3 reductions inplatelets reported in 5% (GIST) and 8% (RCC) ofpatients. Hemorrhage attributed to thrombocytopeniawas not reported in either study. Anemia is also seen,particularly in patients with longer exposure to thedrug, and should be managed in line with local oncol-ogy practice. Hematological effects are often dose-related, and can therefore be managed with dosealterations for severe toxicity.

Other rare but important side-effects

Adrenal toxicity (cortical congestion, hemorrhage ornecrosis) was seen in preclinical studies and was thepredominant reason for the intermittent dosing schedulecurrently recommended for sunitinib. Extensive moni-

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toring of adrenal function has been undertaken in clini-cal trials, with no overt, clinically important adrenalsuppression seen in patients taking sunitinib. Patientstaking sunitinib who undergo stressors such as surgery,trauma, or severe infection should be monitored clini-cally for potential adrenal insufficiency, although thisrisk is considered low.3,4

Rapid tumor necrosis resulting in tumor lysis syn-drome has been described and should be monitored forparticularly in patients with bulky tumors.24,25 Revers-ible posterior leukoencephalopathy syndrome (RPLS),now well described with other VEGF inhibitors includ-ing bevacizumab and sorafenib, has also recently beendescribed in a patient treated with sunitinib.26 RPLS ischaracterized by a reversible syndrome of headache,altered mental functioning, seizures, loss of vision, andcharacteristic findings on MRI.

Dose modification

Sunitinib is available in 12.5 mg, 25 mg and 50 mggelatin capsules. The recommended dosing schedule is50-mg daily for four consecutive weeks, followed by a2 week break, i.e. a 4/2 schedule, to comprise a completecycle of 6 weeks.21 Sunitinib bioavailability is notaffected by food.1 Dose adjustment in 12.5-mg changesis recommended based on individual tolerability.21

Table 3 outlines the suggested dose modifications forhematological and non-hematological side-effects ofvarying severity.

Patients treated in the majority of clinical trials to datehave had a good performance status (ECOG 0 or 1).Patients commencing sunitinib with a poor performancestatus (ECOG 2) may tolerate the drug less well. It isreasonable to consider a starting dose of 37.5 mg/day inthese patients, with a plan to increase their dose to50 mg/day if they tolerate treatment well and improvetheir functional level.

Continuous dosing schedules

Some patients receiving sunitinib describe reduction orresolution of adverse effects during the 2-week breakin the 4/2 schedule. Others describe recrudescenceof cancer-related symptoms. These cyclical changes insymptoms may be ameliorated by use of a continuousdosing schedule.

The clinical development and subsequent registrationstudies for sunitinib in GIST and RCC employed anintermittent dosing schedule based on concerns of accu-mulation of parent drug and metabolites that were seenin preceding preclinical studies. Recent studies in RCC27

and GIST28 have explored continuous dosing of suni-tinib at a dose of 37.5 mg/day, essentially as a way ofnegating the rebound in patients symptoms and changesseen in PET imaging during the 2-week washout period.Although not designed as randomized comparativestudies, data from both the RCC and GIST studies wereconsistent and showed no accumulation of sunitinibover time, with similar efficacy and slightly lowertoxicity rates when compared to the prior intermittentstudies. As expected, treatment interruptions were stillneeded on the continuous dosing schedules, at a slightlyhigher rate than the intermittent regimen. It is importantto note that although the continuous dosing regimenmay be useful in patients with significant rebound symp-toms, sunitinib is currently registered in most countriesto be administered at 50 mg/d in the 4/2 schedule only.

Concomitant medications

Sunitinib is metabolized predominantly by the hepaticcytochrome P450 enzyme CYP3A4. Caution is recom-mended when administering sunitinib in combinationwith known CYP3A4 inducers or inhibitors (Table 4).4

Strong CYP3A4 inhibitors may increase sunitinibplasma concentrations. Selection of an alternate con-comitant medication with no or minimal enzyme inhi-

Table 3 Dose modifications for sunitinib treatment–associated toxicity21

Toxicity Mild to moderate (Grade 1 or 2)Severe and interfering with

function (Grade 3)Life-threatening or requiring

hospitalization (Grade 4)

Non-hematologic Continue at the same dose level Withhold dose until toxicity isgrade � 1 or has returned tobaseline, then resume treatmentat the same dose or reduce thedose by 12.5 mg daily

Withhold dose until toxicity isgrade � 1 or has returned tobaseline, then reduce the dose by12.5 mg daily and resumetreatment, or discontinue

Hematologic(excludinglymphopenia)

Continue at same dose level Withhold dose until toxicity isgrade � 2 or has returned tobaseline, then resume treatmentat the same dose

Withhold dose until toxicity isgrade � 2 or has returned tobaseline, then reduce dose by12.5 mg daily and resumetreatment




bition potential is recommended. Alternatively, a dosereduction for sunitinib to a minimum of 25 mg dailyshould be considered if sunitinib must be coadminis-tered with a strong CYP3A4 inhibitor. CYP3A4 induc-ers may decrease sunitinib plasma concentrations.Selection of an alternate medication with no or minimalenzyme induction potential is recommended. A doseincrease for sunitinib to a maximum of 87.5 mg dailyshould be considered if sunitinib must be coadminis-tered with a CYP3A4 inducer. An increase in doseshould warrant careful monitoring for toxicity.21

Perioperative use of sunitinib

Limited data only are available on the safety of admin-istration of sunitinib in the perioperative setting. Forpatients requiring emergency surgery, sunitinib may notbe able to be stopped preoperatively. For patients under-going planned or elective surgery, sunitinib should bestopped for a minimum of 1 week before surgery (whichis approximately 4 half-lives). Sunitinib can be recom-menced once wound healing has occurred, and ingeneral at least 1 week after surgery. The only clinicaldata addressing safety in a perioperative setting are froma retrospective review of patients with advanced GISTwho were treated with sunitinib at the time of surgery.29

Although sunitinib did not lead to obvious problemswith increased bleeding or wound-related complica-tions, only 26 patients were included in this limited,uncontrolled analysis.

Use in different populations

Clinical trials have included patients from centers inAsia, Europe and America.3,4 No differences in response,tolerability or efficacy have been reported to date relat-ing to ethnicity.30,31 With regard to age, trial results

suggest that sunitinib is as effective and tolerable inpatients 65 years and older as it is in younger adults.21

Sunitinib is contraindicated in pregnancy, and duringbreastfeeding.21 There are little data to date for thepediatric population, however, sunitinib treatment ofmetastatic GIST in 3 pediatric patients after failure ofimatinib showed antitumor activity with manageableside-effects.32 Additionally, there are a number of patientpopulations for whom limited or no data exist to guideclinicians in managing these patients, including patientswith brain metastases, those who have failed a priorVEGF-targeted agent, or those with non-clear cell RCC.

Patient selection

Although sunitinib is simple to administer, adverse effectsmay be complex and it is imperative to ensure patientsafety. Selection of appropriate patients for sunitinibtreatment can sometimes be difficult. In general, adverseeffects become much more common in patients with poorperformance status; bleeding tendency; evidence of coro-nary, cerebrovascular, or peripheral vascular disease; andthose receiving multiple pharmacological agents. In suchpatients, serious consideration should be given as towhether sunitinib therapy is appropriate or whetherother palliative measures may be more suitable. If theadverse clinical factors are reversible, the patient may beable to receive sunitinib safely.

CONCLUSION

Sunitinib malate has proven to be a very useful drug inthe management of patients with imatinib-resistantGIST or advanced RCC. It is likely that sunitinib willalso be shown to have activity in other cancers or in

Table 4 Sunitinib drug interactions

Class Agent Effect Suggestions

CYP3A4 inhibitors ketoconazole, itraconazole,clarithromycin, atazanavir,indinavir, nefazodone, nelfinavir,ritonavir, saquinavir,telithromycin, voriconazole,grapefruit

May increase sunitinibconcentrations.

A dose reduction for sunitinibshould be considered when itmust be coadministered withstrong CYP3A4 inhibitors.Patients should be advisedagainst consuming grapefruit

CYP3A4 inducers dexamethasone, phenytoin,carbamazepine, rifampin,rifabutin, rifapentin,phenobarbital, St. John’s Wort

May decrease sunitinibconcentrations.

Patients receiving sunitinib shouldnot take St. John’s Wortconcomitantly. A dose increasefor sunitinib should beconsidered when it must becoadministered with CYP3A4inducers.

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combination with other therapies. The management ofsuch patients will be complex. The recommendations inthis paper are intended to be a general guide for themanagement of patients receiving sunitinib, and the careof these patients is optimal when it occurs in the contextof an experienced multidisciplinary team.

It is important to emphasize that not all patientsrequire treatment immediately, particularly patients withRCC. Some patients may have other clinical features thatincrease the risk:benefit ratio, or for whom the publisheddata are not applicable because their clinical characteris-tics do not resemble the patients included in the clinicaltrial population. Some patients may have indolentdisease, in which case treatment may be best reserved fora time of clinical need. It remains entirely appropriate toconsider patients for clinical trials either in the first- orsubsequent-line setting, and all treating doctors areencouraged to refer their patients for consideration ofparticipation in a clinical trial if one is available.

ACKNOWLEDGMENTS

IDD is supported in part by a Victorian Cancer AgencyClinician Researcher Fellowship. GAM is a supported inpart by a Cancer Council of Victoria Sir Edward DunlopClinical Research Fellowship.

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