e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0

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Review – Kidney Cancer

Toxicities Associated with the Administration of Sorafenib,Sunitinib, and Temsirolimus and Their Management inPatients with Metastatic Renal Cell Carcinoma

Naeem Bhojani a,b, Claudio Jeldres a,b, Jean-Jacques Patard c, Paul Perrotte b,Nazareno Suardi a,d, Georg Hutterer a,e, Francois Patenaude f, Stephane Oudard g,Pierre I. Karakiewicz a,b,*aCancer Prognostics and Health Outcomes Unit, University of Montreal, Montreal, QC, CanadabDepartment of Urology, University of Montreal Health Center (CHUM), Montreal, QC, CanadacDepartment of Urology, Rennes 1 University Hospital, Rennes, FrancedDepartment of Urology, Vita-Salute University San Raffaele, Milan, ItalyeDepartment of Urology, Graz Medical University, Graz, AustriafCancer Prevention Centre, McGill University, Montreal, QC, CanadagMedical Oncology Department, Gorges Pompidou European Hospital, Paris, France

Article info

Article history:Accepted November 13, 2007Published online ahead ofprint on November 26, 2007

Keywords:Side effectsSorafenibSunitinibTemsirolimus

Abstract

Objective: To provide a systematic review of the side effects associatedwith sorafenib, sunitinib, and temsirolimus and to provide an outline ofpossible preventive or therapeutic measures.Methods: We performed a PubMed-based systematic review of sideeffects associated with the three agents and relied on product mono-graphs and prescribing information to provide an outline of treatmentsaimed at reducing these toxicities.Results: Side effects range from <1% to 72%. Grade 3/4 side effects areless common and range from <1% to 13% for sorafenib, <1% to 16% forsunitinib, and 1% to 20% for temsirolimus. Overall, sunitinib causes themost grade 3/4 side effects and sorafenib causes the fewest grade 3/4 sideeffects, although head-to-head trials are required to compare safetyprofiles of all three kinase inhibitors. Virtually all side effects can bemanaged effectively.

ntion, recognition, and prompt management of sideimportance and avoid unnecessary dose reductions,

Conclusion: Preveeffects are of key

rmine treatment efficacy.ociation of Urology. Published by Elsevier B.V. All rights reserved.

which may unde# 2007 European Ass

* Corresponding author. Cancer Prognostics and Health Outcomes Unit, University ofMontreal Health Center (CHUM), 1058, rue St-Denis, Montreal, QC, Canada H2X 3J4.Tel. +1 514 890 8000 35336; Fax: +1 514 412 7363.E-mail address: pierre.karakiewicz@umontreal.ca (P.I. Karakiewicz).

0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.11.037

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0918

1. Introduction

Recently, the United States Food and Drug Admin-istration approved three targeted therapies for thetreatment of metastatic renal cell carcinoma(mRCC). Sorafenib (Nexavar) significantly prolongedthe progression-free survival in 903 patients versusplacebo [1]. Sunitinib (Sutent) also significantlyimproved progression-free survival when comparedto interferon-a (IFN-a) in 750 randomized patients[2]. Finally, temsirolimus (Torisel) increased medianoverall and progression-free survival versus IFN-a orIFN-a/temsirolimus combination [3]. However, allthree agents were also associated with non-negli-gible toxicity profiles [4,5]. We performed a com-prehensive search of all pertinent studies, withthe intent of identifying the main toxicities andwith the goal of providing an outline of availablepreventive or therapeutic measures.

2. Methods

We performed a systematic English language, abstract-based

literature review using the key words ‘‘sorafenib,’’ ‘‘sunitinib,’’

‘‘temsirolimus,’’ ‘‘toxicity,’’ and ‘‘adverse effects.’’ Temporal

limits were not applied to our search because all three agents

represent novel molecules. Subject and outcome of interest,

design type, sample size, pertinence, and quality and detail of

reporting were the indicators of manuscript quality. Due to the

paucity of phase 1, 2, and 3 studies on kinase inhibitors, all

such studies were considered. As a result, strict quality criteria

such as suggested by Oxman et al could not be applied [6]. The

search was completed by three of the authors (N.B., C.J., and

P.K.). It was complemented with the Canadian product

monographs for sorafenib and sunitinib and the American

temsirolimus prescribing information.

The toxicities and side effects for each agent were

tabulated according to study phases (1 vs. 2 vs. 3) and organ

system. For each specific toxicity or toxicity group, we outlined

a structured approach to early symptom recognition, preven-

tion, and management.

3. Results and discussion

3.1. Systematic literature review

Using each agent’s generic name we searched threedatabases: PubMed, Cancerlit, and Cochrane. ThePubMed search revealed 372, 397, and 218 articles forsunitinib, sorafenib, and temsirolimus, respectively,versus 52, 76, and 23 for Cancerlit and 0 forCochrane. A PubMed search for the most commonadverse effects (fatigue, mucositis, diarrhea, nausea,rash, anemia, and hypertension) combined witheach agent found between 0 and 22 articles per agentand adverse effect combination. All of the retrieved

articles were considered. A PubMed Mesh searchproduced 224 articles for sunitinib, 253 articles forsorafenib, and 146 articles for temsirolimus. Subse-quently, a combined PubMed Mesh search, usingeach agent as a subject heading combined withadverse effects as an additional subject heading,resulted in 59, 64, and 27 articles for sunitinib,sorafenib, and temsirolimus, respectively. Again, allarticles were considered for inclusion. Finally, ahand search of the 2002–2007 American Society ofClinical Oncology, American Urological Association,and the European Association of Urology abstractsresulted in 36 additional entries. Based on contentconsiderations none qualified for inclusion. Finally,15 articles qualified for compilation of side effects[1–3,7–18] according to the above selection criteria.Phase 3 studies represent grade A level of evidenceversus grade C for phase 1 and 2 studies [19]. Relativeto phase 1 and 2 studies, toxicity rates from phase 3studies are most reliable, primarily because of theirsample size considerations. Therefore, the results ofphase 3 studies should ideally be given the strongestconsideration.

3.2. Phase 1 studies

The safety and toxicity of sorafenib was investi-gated in four phase 1 (n = 173) studies. Doses rangedfrom 50 to 800 mg once (QD) or twice (BID) daily[7–10]. The maximum tolerated dose (MTD) was400 mg given continuously BID. Grade 3 or higherdose-limiting toxicities (DLTs) consisted of diar-rhea (2 of 6 at 800 mg BID), fatigue (1 of 6 at 800 mgBID), and skin toxicity (4 of 14 at 600 mg BID),according to the National Cancer Institute CommonToxicity Criteria (NCICTC) version 2.0 [20]. Basedon efficacy versus toxicity ratio, the 400-mg BIDdosage, associated with a manageable toxicityprofile, was recommended as the target dose forfuture trials.

The safety and toxicity of sunitinib were assessedin a phase 1 trial of 28 patients (NCICTC version 2.0)[11,20]. Doses ranged from 50 mg every other day to150 mg QD. Grade 3 or higher DLTs occurred at aMTD�75 mg and were reversible (fatigue, hyperten-sion, and hand–foot syndrome). Based on manage-able toxicity, a 50-mg QD dosing schedule deliveredfor 4 wk, with a 2-wk rest period, was recommended.At this dosing schedule mouth soreness, edema, andthrombocytopenia represented the main adverseeffects. Asthenia affected two of nine patients andhematologic toxicities mostly consisted of throm-bocytopenia (2 of 9 patients) and neutropenia (3 of 9patients). Most hematologic toxicities and astheniaresolved during the 2-wk rest period. At higher

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0 919

doses, minor skin toxicities and various degrees ofreversible hair depigmentation were also seen intwo of three patients.

Phase 1 safety and toxicity of temsirolimus (givenweekly at intravenous doses ranging from 7.5 to220 mg/m2) were investigated in 24 patients [12].Toxicity was assessed during the first four infusions(NCICTC version 3.0) [21]. No grade 3 or 4 toxicitieswere seen up to 22.5 mg/m2. At 34 mg/m2, grade 3neutropenia, thrombocytopenia, and hypophospha-temia affected one patient, who was exposed toextensive prior radiotherapy. Further dose escala-tion revealed one case of grade 3 thrombocytopenia,asthenia, and diarrhea. No additional DLTs wererecorded up to 220 mg/m2 at which dose grade 2euphoria and insomnia as well as grade 3 depres-sion, stomatitis, and transaminase elevationsoccurred. Toxicities were reversible after 2 wk oftreatment discontinuation. Of patients exposed totemsirolimus (doses 7.5–165 mg/m2), grade 3/4 toxi-cities were distributed as follows: 7% dermatologictoxicity, 7% asthenia, 13% thrombocytopenia, 7%diarrhea, and 20% hypercholesterolemia. Based onthese data, weekly intravenous doses of 25, 75, and250 mg were recommended for further testing.

3.3. Phase 2 studies

A phase 2 trial of sorafenib 400 mg BID for 12 wk in202 patients with mRCC revealed fatigue (73% ofpatients), rash/desquamation (66%), hand–foot skinreaction (62%), pain (58%), diarrhea (58%), andhypertension (43%) (NCICTC version 2.0) [13,20].Overall, 53% of patients reported any grade 3 toxicityand 12% had any grade 4 toxicity. Any grade 3toxicities were cardiovascular (34%), hypertension(31%), dermatologic/skin (17%), hand–foot skinreactions (13%), gastrointestinal (13%), laboratory(12%), and pain (11%). Grade 3 febrile neutropeniaaffected 5% of patients and no grade 4 febrileneutropenia occurred. The remaining grade 3toxicities affected fewer than 10% of patients. Anygrade 4 toxicities were distributed as follows:laboratory 5%, neurologic 2%, pulmonary 2%,followed by blood, bone marrow, hemoglobin, andpain (1% each). No deaths were directly attributableto drug toxicity.

In a phase 2 trial, sunitinib 50 mg QD wasadministered to 106 patients with mRCC in 4 wkon/2 wk off cycles [14]. Fatigue (28%) and diarrhea(20%) were most frequent (NCICTC version 3.0) [21].The most frequent grade 3 side effects includedfatigue (11%), hand–food syndrome (7%), hyperten-sion (6%), and stomatitis (5%). Grade 3 and 4 anemiaaffected, respectively, 4% and 2% versus 14% and 2%

for, respectively, grade 3 and 4 neutropenia. Nocases of associated fever or sepsis occurred. Eightpatients (4.7%) experienced a decline in left ven-tricular ejection fraction (LVEF). However, noneprogressed to congestive heart failure. A singlefatality (myocardial infarction) was possibly relatedto sunitinib.

In a phase 2 temsirolimus study, 111 patients withmRCC were randomized to weekly intravenoustemsirolimus (25 vs. 75 vs. 250 mg) [15]. The mostcommon toxicities [20] were maculopapular rash(76%), mucositis (70%), asthenia (50%), and nausea(43%). The most frequent grade 3/4 toxicitiesincluded hyperglycemia (17%), hypophosphatemia(13%), anemia (9%), and hypertriglyceridemia (6%)(NCICTC version 3.0) [21]. Neutropenia was notreported. Six patients (5.4%) developed nonspecificpneumonitis (not graded). No patient died fromtemsirolimus-related toxicities.

3.4. Phase 3 studies

A phase 3 sorafenib study was conducted in 903patients previously treated with immunotherapywho were randomized to placebo versus sorafenib(400 mg BID) [1]. The most common adverse eventsof any grade were diarrhea (43%), rash or desqua-mation (40%), fatigue (37%), hand–foot skin reaction(30%), alopecia (27%), and nausea (23%) (NCICTCversion 3.0) [21]. The most frequent grade 3/4toxicities included hand–foot skin reactions (6%),fatigue (5%), dyspnea (4%), and hypertension (4%).Grade 3/4 anemia occurred in 3% of patients andgrade 3/4 lymphopenia occurred in 13% of patients.Neutropenia was not reported. Cardiac ischemia orinfarction occurred in 3% of patients.

A phase 3 trial randomized 750 patients to first-line sunitinib (50 mg QD, 4 wk on/2 wk off) versusIFN-a [2]. The most common sunitinib adverseevents were diarrhea (53%), fatigue (51%), nausea(44%), stomatitis (25%), vomiting (24%), and hyper-tension (24%) (NCICTC version 3.0) [21]. The maingrade 3 toxicities were hypertension (8%), fatigue(7%), and diarrhea (5%). The only grade 4 toxicity wasrash in 1%. The most frequent grade 3 laboratoryabnormalities included increased lipase (13%),lymphopenia (12%), neutropenia (11%), thrombocy-topenia (6%), and leukopenia (5%). Important grade 4laboratory adverse events consisted of anemia (1%)and neutropenia (1%).

A phase 3 temsirolimus study randomized 626patients with previously untreated, poor-prognosismRCC to temsirolimus (25 mg weekly) versus IFN-a

and temsirolimus (15 mg weekly) versus IFN-a alone[3]. The main temsirolimus adverse effects of any

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0920

grade consisted of asthenia (51%), rash (46%),anemia (45%), nausea (37%), and anorexia (32%).Grade 3/4 toxicities consisted of asthenia (11%),dyspnea (9%), pain (5%), and infection (5%) in thetemsirolimus group compared to 26%, 6%, 2%, and4%, respectively, in the IFN-a group (NCICTC version3.0) [21]. The most common grade 3/4 adverselaboratory effects included anemia (20%), hypergly-cemia (11%), hyperlipidemia (3%), neutropenia (3%),and elevated serum creatinine (3%) in the temsir-olimus group compared to 22%, 2%, 1%, 7%, and 1%,respectively, in the IFN-a group.

Table 1 – Most common adverse reactions of sunitinib, sorafe

Adverse reactions Sorafenib (Trade name:Nexavar) Dose: 400 mg BID

SS

All grades (%) Grade 3/4 (%) All g

Systemic

Fatigue/asthenia 37 5

Hypothyroidism — NA

Cardiac

Hypertension 17 4

Declined LVEF — *

Respiratory

Dyspnea 14 4

Hematologic

Bleeding 15 2

Gastrointestinal

Diarrhea 43 2

Nausea 23 <1

Vomiting 16 <1

Dyspepsia — —

Anorexia 16 <1

Altered taste — —

Abdominal pain 11 2

Cutaneous

Rash 40 <1

Hand–foot syndrome 30 6

Alopecia 27 <1

Mucositis/stomatitis 21 6

Skin discoloration — —

Pruritus 19 <1

Edema — —

Laboratory

Neutropenia 18 5

Hypophosphatemia 45 13

Elevated lipase 41 12

Lymphopenia 23 13

Anemia 44 2

Thrombocytopenia 12 1

" creatinine — —

" triglycerides — —

" total cholesterol — —

Hyperglycemia — —

BID = twice daily; QD = daily; NA = not available; LVEF = left ventricular e* Cardiac ischemia or infarction occurred in 3% of patients.y One third of all bleeding episodes consisted of epistaxis.

Rini et al assessed the effect of sunitinib onthyroid function in 66 patients with mRCC [22]. Oneor more thyroid function abnormalities wererecorded in 85% of patients. Elevated thyroid-stimulating hormone (TSH) and decreased T3, aT4,and free thyroxine levels affected 70%, 68%, 23%,and 30% of patients, respectively. Of 17 (26%)patients who received thyroid hormone replace-ment therapy, 9 (53%) demonstrated symptomaticimprovement. Additionally, macrocytosis and coba-lamin deficiency was reported with sunitinib after atreatment period of 3–4 mo [23]. A synopsis of

nib, and temsirolimus [1–3,16–18,21,22]

unitinib (Trade name:utent) Dose: 50 mg QD

Temsirolimus (Trade name:Torisel) Dose: 25 mg weekly

rades (%) Grade 3/4 (%) All grades (%) Grade 3/4 (%)

58 7 51 11

71 NA — NA

24 8 7 —

10 2 — NA

16 1 28 9

26y <1 — —

53 5 27 <1

44 3 37 2

24 4 19 2

28 1 — —

28 1 32 3

44 <1 15 0

22 3 21 4

19 2 47 4

20 5 — —

— — — —

45 3 41 3

16 0 — —

— — 19 1

11 1 35 3

72 12 7 3

36 5 8 5

52 16 — —

60 12 5 —

71 4 45 20

65 8 14 1

66 1 14 3

— — 27 4

— — 24 1

18 4 26 11

jection fraction.

Table 2 – Medical management of most common hematologic adverse effects of sorafenib, sunitinib, and temsirolimus[16–18,37]

Adverse reactions Monitoring Pharmacologicinterventions

Thrombocytopenia �Avoidance of bruises, cuts, and burns �Supportive and/or dose

modification/interruption�Treatment of constipation

�Avoidance of aspirin, ibuprofen, or nonsteroidal

anti-inflammatory medication (acetaminophen can be used)

Neutropenia �1.4 � 109 �Complete blood count every 2 wk or daily if febrile neutropenia

�Counseling to prevent infections: wash hands, etc.

�Treatment interruption

Lymphopenia �Observation

Anemia �Threshold for initiation of erythropoietic

proteins: hemoglobin 9–11 g/dl

�Complete blood counts should be done

at the first visit and then on

week 2, 4, 8, and 12. Thereafter, complete blood counts should be

done every 4 wk or according to symptoms.

�Thyroid function should be evaluated

(thyroid-stimulating hormone and T4)

If hemoglobin <9 g/dl, then patient should be

evaluated for need for transfusions.

Target hemoglobin level is 12–13 g/dl.

Bleeding �Complete blood count and physical examination �Do not stop anticoagulation

therapy unless major bleeding�Avoidance of intense physical activities or

activities with an increased risk of bleeding �Temporary discontinuation of

sunitinib or dose delay

�No discontinuation for epistaxis

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0 921

product monographs with reported product-specificside effects, tabulated by severity, is provided inTable 1. A cumulative count of all grade 3/4 toxicitiesfor each medication indicates that sunitinib isassociated with highest incidence of grade 3/4toxicities and that sorafenib is associated with thelowest rate. However, head-to-head trials that areperformed in patients with the same entry criteria

Table 3 – Medical management of most common systemic ortemsirolimus [16–18,22,25,26]

Adverse reactions Monitoring

Fatigue �Rule out hypothyroidism,

anemia, or depression

Depression �Rule out organic cause

Dyspnea �Patients should be monitored

for possible respiratory symptoms

Thyroid dysfunction

and hypothyroidism

�TSH every 2–3 mo during treatment

QD = daily; BID = twice daily; TSH = thyroid-stimulating hormone.

are required to objectively and validly comparesafety profiles of the three kinase inhibitors [24].

3.5. Management of drug-related toxicities

3.5.1. Systemic toxicities

Fatigue management is supportive. Grade 3/4fatigue requires treatment interruption or dose

endocrinologic adverse effects of sorafenib, sunitinib, and

Pharmacologicinterventions

�Supportive care

�Psychiatric consultation

�Paroxetine: starting dose 20 mg QD

�Venlafaxine: starting dose 37.5 mg BID

�Chest x-ray if respiratory symptoms develop in individuals

taking temsirolimus to rule out interstitial pneumonitis

�Levothyroxine:

1. Usual starting dosage for adults >50 yr without cardiac

disease or <50 yr with cardiac disease: 25–50 mg QD

2. For adults >50 yr with cardiac disease: 12.5–25 mg QD

Dose adjustments are needed every 6–8 wk, based on clinical

and laboratory parameters.

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0922

adjustment. All agents cause anemia. Thus, com-plete blood counts are indicated at the first, second,and fourth week visits followed by every 4 wk oraccording to symptoms (Table 2). Transfusions arereserved for symptomatic patients or hemoglobinlevel <9 g/dl. Primary tumor or metastases bleedsmay cause anemia and may require embolization orsurgery. However, the most common cause ofanemia remains that of chronic disease. Althoughobjective data are unavailable, therapy should bediscontinued for 2–4 wk prior to surgery, until 1–2 wkthereafter.

Hypothyroidism may cause anemia in patientsexposed to sunitinib and TSH levels should bechecked prior to treatment initiation and then every2–3 mo [25] (Table 3). Symptomatic patients withelevated TSH require levothyroxine, with doseadjustments every 6–8 wk, based on clinical andlaboratory parameters. Fatigue may be accompa-nied by dyspnea, which may also require dose

Table 4 – Medical management of most common cardiac adver

Adverse reactions Monitoring

Hypertension �Blood pressure monitoring weekly during

the first 6 wk of therapy.

�For patients with preexisting hypertension

weekly blood pressure in a home setting

Decreased LVEF �For patients with cardiac risk factors: basel

evaluation of ejection fraction: echocardiog

electrocardiogram

QT-interval prolongation �Sunitinib should be used with caution in p

history of QT-interval prolongation or who

drugs that increase the QT interval

�Periodic monitoring with electrocardiogram

electrolytes is recommended

D = daily; BID = twice daily; HCTZ = hydrochlorothiazide; LVEF = left vent

reductions. Chest x-rays might detect interstitialpneumonitis in patients exposed to temsirolimus[15].

The reported prevalence of depression in termin-ally ill cancer patients is 13–26% and may causefatigue [26]. The specific rate in those with mRCC isunknown. Suspicion of depression warrants apsychiatric consultation. Treatment usually con-sists of selective serotonin reuptake inhibitors(SSRIs), such as paroxetine (starting dose, 20 mgQD) or venlafaxine (starting dose, 37.5 mg BID),which are better tolerated than tricyclic antidepres-sants.

3.5.2. Cardiovascular toxicities

The exact mechanism of kinase inhibitors inducedhypertension is unknown. A direct effect at the levelof the vasculature is possible [5,27]. Blood pressureshould be monitored weekly, ideally at the patient’shome [16,17]. National or international guidelines

se effects of sorafenib, sunitinib, and temsirolimus [16–18]

Pharmacologic interventions

�Standard antihypertensive therapy (eg, refer to

the Canadian hypertension guidelines

at www.hypertension.ca):

: �Angiotensin II receptor blockers, b-blockers,

and diuretics

�Optimal drug choices (no hepatic metabolism):

�Telmisartan (20–80 mg QD)

�Valsartan (80–320 mg QD)

�Atenolol (50–100 mg QD)

�HCTZ (12.5–100 mg QD)

Example of possible protocol:

Begin with HCTZ 12.5 mg QD and increase

until maximum/tolerable dose. If hypertension

remains uncontrolled, add another medication

(ie, atenolol, valsartan or telmisartan). Note:

Non-dihydropyridine calcium channel blockers

(verapamil, diltiazem) are contraindicated

(CYP3A4 inhibitor: may increase the levels/effects

of sunitinib).

However, if blood pressure difficult to control:

�Amlodipine (2.5–10 mg QD)

�Severe hypertension: temporary suspension

of the drug

ine

raphy,

�Stop medication if congestive heart failure

symptoms appear.

�Dose should be interrupted or reduced in

patients without clinical evidence of congestive

heart failure but with an ejection fraction

<50% and >20% below baseline.

atients with a

are taking

and

ricular ejection fraction.

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0 923

(www.hypertension.ca) provide examples of hyper-tension management (Table 4). Angiotensin IIreceptor blockers (ARBs; valsartan 80–320 mg QD),b-blockers (atenolol 50–100 mg QD), and diuretics(hydrochlorothiazide 12.5–100 mg QD) can be usedalone or in combination. Non-dihydropyridine cal-cium channel blockers, verapamil and diltiazem, arecontraindicated. However, because amlodipine hasminor 3A4 metabolism, it can be used if bloodpressure is difficult to control. Angiotensin-convert-ing enzyme inhibitors may induce cough in somecases, which may falsely suggest lung toxicity ormetastases.

Increased mortality related to intracranialhemorrhage (ICH) was observed in individuals

Table 5 – Medical management of most common gastrointestin[16–18,29]

Adverse reactions Initial nonpharmacologic m

Diarrhea �Avoidance of foods that would aggrav

the diarrhea (spicy, fatty foods, caffei

�Avoidance of stool softeners and fiber

�Aggressive oral rehydration with fluid

containing water, salt, and sugar

Nausea and vomiting �Eat and drink often in small amounts

�Drink plenty of liquids

Dyspepsia �Avoidance of meals before bedtime

�Avoidance of reflux-inducing foods:

peppermint, chocolate, coffee, alcoho

Anorexia �No evidence that nutritional counselin

Rarely requires dose modification �Supplementation with parenteral or e

feeding has only limited efficacy (Ens

Altered taste Supportive care

PO = orally; QD = daily; BID: twice daily.

with mRCC treated with sunitinib or sorafenib[28]. Two sunitinib patients (one with baselinehypertension) and three sorafenib patients (twowith baseline hypertension) developed ICH, whichdemonstrates the importance of controlling thepatient’s hypertension before initiating kinaseinhibitors and the importance of regular arterialpressure recordings.

Declined LVEF affected 10% of patients receivingsunitinib [14]. Baseline echocardiography of LVEF isrecommended for patients with existing risk factorswho are given sunitinib. If symptoms occur or ifLVEF decreases to<50% or decreases by�20% belowbaseline, sunitinib should be interrupted or at leastthe dose reduced. Electrocardiographic monitoring

al adverse effects of sorafenib, sunitinib, and temsirolimus

easures Pharmacologic interventions

ate

ne)

�Loperamide (Imodium) and

diphenoxylate (Lomotil)

supplements Standard dose (Imodium): initial 4 mg doses

followed by 2 mg every 4 h or after every

loose stool

s

More aggressive: 4 mg initially,

then 2 mg every 2 h

�Cholestyramine: 4 g PO 30 min prior to

treatment and every 6 h as needed

�Premedication with antiemetics to

limit treatment related nausea and vomiting.

First-line:

�Dimenhydrinate (Gravol): 50–100 mg

PO every 6 h

Second-line:

�Prochlorperazine (Stemetil): 5–10 mg

3–4 times/d (maximum: 40 mg/d)

Third-line:

�Granisetron (Kytil): 2 mg QD

�Ondansetron (Zofran): 8 mg every

12 h starting 30 min before treatment

Use with particular care: may be associated

with QT/QTc-interval prolongation, which

may increase the risk of torsades de pointes.

�As well, dexamethasone pretreatment:

can be used.

�Antacid: Aluminum hydroxide/magnesium

hydroxide (Maalox) 30 ml PO every 4–6 h

l �Histamine H2 antagonist: famotidine

(Pepcid) 20 mg PO BID

�Proton pump inhibitor: pantoprazole

(Pantoloc) 40 mg PO QD

g has any benefit �Progestational agents: megestrol

acetate (160–800 mg QD)

nteral

ure, Boost)

�Corticosteroids: dexamethasone

(Dexasone) 4 mg QD in morning

(lower doses may also be effective)

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0924

is recommended in patients with a history ofQT-interval prolongation and in those exposed tomedications that predispose to QT-interval prolon-gation (Table 4) [17].

3.5.3. Renal toxicities

Kinase inhibitor-associated proteinuria and edemaare rare. However, proteinuria may occur afterprolonged exposure.

3.5.4. Gastrointestinal toxicities

Either loperamide or diphenoxylate relievesdiarrhea. Dietary adjustments and rehydrationshould accompany one of these agents [17].Cholestyramine, a cholesterol-lowering agent thatdecreases motility and increases reabsorption,may decrease the severity of diarrhea if taken

Table 6 – Medical management of most common cutaneous a[16–18,31]

Adverse reactions Initial nonpharmacologic measures

Rash/desquamation �Grade 1: moisturizing cream BID

�Aveeno lotions and soap

�Antidandruff shampoo

�Loose clothing

�Avoidance of direct sunlight,

detergents, antibacterial soaps,

alcohol-based perfume lotion

�Use sun protection of at least 30 SPF

Hand–foot syndrome

(acral erythema)

�Manicure and pedicure before and

during treatment

�During treatment: shock absorbers for

pressure points, sandals

�Application of an alcohol-free moisturize

immediately after bathing

Mucositis/stomatitis �Routine mouth care: gentle cleansing,

removal of dentures

May enhance or

provoke anorexia

�Mouth wash with weak solution of

salt and baking soda

(1/2 teaspoon of salt + 1 teaspoon

of baking soda, in 250 ml water: swish,

gargle and spit)

�Diet with foods that do not require

significant chewing

Pruritus �Appropriate skin care

�Avoidance of scratching

�Use of an humidifier,

cool environment

�Avoidance of hot showers

�Use of mild soaps and Aveeno lotion

Alopecia Supportive care

Skin discoloration Supportive care

QD = daily; PO = orally; BID = twice daily.

30 min prior to sorafenib or sunitinib dosing(Table 5).

Dimenhydrinate relieves nausea and vomiting.Alternatives include prochlorperazine and ondan-setron, as second- and third-line therapy, respec-tively, due to cost considerations. Around-the-clockdosing, as opposed to as-needed dosing, mayincrease effectiveness (Table 5).

Dyspepsia should prompt avoidance of reflux-inducing foods and is complemented with eitheraluminum and magnesium hydroxide (may causediarrhea) suspension (30 ml orally every 4–6 h), orfamotidine (20 mg orally BID) or pantoprazole, or acombination of drugs (Table 5).

A progestational agent (megestrol acetate 160–800 mg QD) or dexamethasone (4 mg QD) may helpwith appetite (Table 5) [29].

dverse effects of sorafenib, sunitinib, and temsirolimus

Pharmacologic interventions

�Grade 1–2: hydrocortisone 1% cream

�Grade 3: prednisone:

25 mg PO daily for 2 d, then 10 mg PO QD for 7–14 days

�Grade 4: dermatology referral

�Corticosteroids have no proven efficacy

�Treatment delay and adjustments if grade 3 toxicity

r

Without fungal infection:

�Mucosal coating agents (Orabase, Gelclair),

�Topical lidocaine solutions combinations of topical

lidocaine and mucosal-coating agents

(Magic mouthwash [see Appendix 5]).

With fungal infection (oral candidasis):

�Oral fluconazole (Diflucan): 200 mg BID for 7–14 d OR

�Local clotrimazole (Canesten topical):

Prophylaxis: 10 mg troche dissolved 3 times daily.

Treatment: 10 mg troche dissolved slowly

5 times daily for 14 d

Note: Ketoconazole is contraindicated because it

may increase serum kinase inhibitor concentrations.

�Topical antipruritics, eg, camphor-based lotion,

oatmeal bath (Aveeno)

�Antihistamines: H1 antagonists: hydroxyzine

(Atarax), diphenhydramine (Benadryl)

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0 925

3.5.5. Cutaneous toxicities

Skin toxicity most likely results from epidermalgrowth factor receptor (EGFR) inhibition in the skinvia Raf kinases [30]. Prevention of pruritus, rash, anddesquamation requires avoidance of direct sunlight,use of sun protection creams, and around-the-clockuse of moisturizing-barrier creams [17]. Colloidaloatmeal lotion and gentle soaps and shampoos(Aveeno) may reduce the risk and the severity ofpruritus and desquamation. If desquamationoccurs, 1% hydrocortisone cream should be appliedat least four times daily. Topical or oral diphenhy-dramine or oral hydroxyzine represent antipruriticagents of choice (Table 6) [17]. For grade 3 toxicity,oral prednisone (starting dose of 25 mg BID for 2 d,followed by 10 mg QD) is added. Treatment inter-ruption, dose reduction, or dermatology referralshould be considered, if these measures fail.

Hand–foot syndrome can be prevented withregular manicures and pedicures [31]. Excessivepressure on bony prominences should be avoidedby adjusting the level of physical activity and by

Table 7 – Medical management of most common laboratory a[16–18]

Adverse reactions Monitoring

Hypophosphatemia �Monitor phosphate level during repla

Elevated lipase and amylase �Observation with or without supporti

�Alcohol should be prohibited

Elevated cholesterol

and/or triglycerides

�Patients may require initiation of, or

of lipid-lowering medications.

�Patients treated with temsirolimus sh

for serum cholesterol and triglyceride

during treatment (weekly for the first

Glucose �May be affected in some diabetic pati

to check blood glucose levels. Patient

report any excessive thirst or any inc

frequency of urination.

�Glucose levels should be checked wee

the first month of treatment.

�In patients taking temsirolimus there

likelihood that insulin or oral hypogly

have to be introduced (or the dose m

to control patient’s glucose levels.

QD = daily; HMG-CoA = b-hydroxy-b-methylglutaryl-coenzyme A; BID = t

wearing appropriate footwear (shock-absorbingsoles, etc) [31]. Skin care (see above) should comple-ment these measures (Table 6). Minor subungualsplinter hemorrhages have been reported withsorafenib and sunitinib but require no treatment.

Oral mucositis and stomatitis may be preventedwith rigorous oral hygiene, use of salt and bakingsoda mouthwash solutions, and a soft diet [17].Grade 1 or higher oral mucositis/stomatitis requiresmixtures of mucosal-coating agents and localanesthetics (eg, Magic mouthwash [see Appendix2 for formula]). Oral candidiasis may call for topicalclotrimazole troches (10 mg, 5 times daily) or oralfluconazole (200 mg tablets for 7–14 d). Ketoconazoleis contraindicated because it may increase drugconcentrations (Table 6). Grade 3 mucositis orstomatitis requires dose reduction or treatmentinterruption.

3.5.6. Laboratory toxicities

Febrile neutropenia represents the most life-threa-tening hematologic complication and invariably

dverse effects of sorafenib, sunitinib, and temsirolimus

Pharmacologic interventions

cement �Oral phosphate replacement:

2.5–3.5 g QD in 3–4 daily divided

doses (may cause loose bowel

movements and cramps)

ve measures

increase in dose

ould be tested

levels before and

month).

�Recommended starting doses:

Pravastatin: 10–80 mg QD

Other HMG-CoA reductase inhibitors

are substrates for CYP450 3A4 and

should be followed closely when

taken with any of the kinase inhibitors.

ents. It is important

s should be advised to

rease in the volume or

kly for at least

is an increased

cemic agents would

ay have to be elevated)

�Recommended starting doses:

Metformin: 500 mg BID

�If glyburide is necessary the dose

of temsirolimus must be adjusted

(decreased) because glyburide is an

inhibitor of CYP450 3A4

wice daily.

Table 8 – Recommended dose modifications secondary to laboratory toxicities [16]

Grade 1 Grade 2 Grade 3 Grade 4

�Continue same

dose level

�Continue same

dose level

�Withhold dose until toxicity grade is �2,

then resume initial dose

�Withhold dose until toxicity grade is �2

Special considerations:

�Decrease the dose by one level

�Recurrent neutropenia or thrombocytopenia

after �5 d: dose reduction on the next cycle

�Lymphopenia or anemia: no dose modification

Special considerations:

�Lymphopenia: no dose modification

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0926

should prompt treatment interruption. Treatmentmay be restarted at reduced dose once grade 2 orlower toxicity level is reached. The standardapproach for afebrile neutropenia consists of treat-ment interruption until the neutrophil count nor-malizes (returns to grade 2 [<1.5–1.0 � 109/l]). A dosereduction at the next treatment cycle is warranted(Table 2).

Grade 3/4 hypophosphatemia may have severeconsequences, including encephalopathy, conges-tive heart failure, ileus, rhabdomyolysis, hemolysis,and defective clot retraction. Phosphate monitoringis recommended at each visit. Typically, hypopho-sphatemia is a benign metabolic problem. Someclinicians rely on phosphate replacement only inpresence of myopathy or renal failure. Oral phos-phate replacement can be accomplished in 3–4 dailydivided doses of 2.5–3.5 g along with daily phosphatedosing (Table 7).

Mammalian target of rapamycin is involved in theinsulin signaling pathway and its inhibition bytemsirolimus may cause hyperglycemia [32,33].

Table 9 – Dose modifications [16–18]

General recommendations for sorafenib dose modifications:

�Modification of 400 mg recommended (reduction to 200 mg BID).

�If further reduction is required, sorafenib may be reduced to 200 mg QD

�A second option is to reduce one dose to 200 mg while maintaining the

decrease to 200 mg BID.

General recommendations for sunitinib dose modifications:

�Modification of 12.5 mg (increase or reduction) recommended based on

�If more than two consecutive dose reductions are required, it is prefera

�Recovery to acceptable levels of toxicity must occur within 4 wk to allo

�Start of the next sunitinib schedule may be delayed by 2 wk if addition

treatment-associated toxicity.

�Re-escalation back to the previous dose level is suggested in the absen

grade 2 or higher, treatment-related toxicities in the previous cycle.

�A dose reduction to a minimum of 37.5 mg daily should be considered

�A dose increase to a maximum of 87.5 mg daily should be considered i

General recommendations for temsirolimus dose modifications:

�Dose adjustments should be based on safety assessments and should i

�Temsirolimus should be held if absolute neutrophil count goes below 1

grade 3 [13] or greater adverse reactions.

�Once the abnormality has dissipated to a grade 2 or less, temsirolimus

�The dose can be reduced again if necessary; however, the lowest dose

�In general, patients should be taken off temsirolimus if they fail to reco

BID = twice daily; QD = daily.

Indeed, hyperglycemia and hypercholesterolemiaare associated with temsirolimus exposure andshould be monitored weekly for at least the firstmonth of treatment [18]. Administration of choles-terol-lowering agents (pravastatin 10–80 mg QD)may be required. Similarly, glucose-lowering agents(metformin 500 mg BID) might be required. Some b-hydroxy-b-methylglutaryl-coenzyme A (HMG-CoA)reductase inhibitors are substrates of CYP450 3A4and are considered a relative contraindication(Table 7). Nonetheless, several temsirolimus-treatedpatients already receiving atorvastatin (Lipitor, anHMG-CoA reductase inhibitor) had no added toxi-city.

3.5.7. Dose modifications

The recommended dose reduction for sorafenib is200 mg BID or even 200 mg QD versus 400 mg BID[16]. An alternative 400/200 mg dosing is alsopossible (Tables 8 and 9). For sunitinib, 12.5-mgsequential dose reductions are recommended fromthe 50-mg full dose [17]. If more than two con-

.

second dose at 400 mg. If toxicity persists then one can

individual safety and tolerability.

ble to discontinue the patient’s sunitinib therapy.

w sunitinib continuation.

al time is required for the patient to recover from

ce of hematologic grade 3 or higher, or nonhematologic

if sunitinib must be coadministered with a strong CYP3A4 inhibitor.

f sunitinib must be coadministered with a CYP3A4 inducer.

nclude laboratory and clinical assessments.

000/mm3, platelet count goes below 75000/mm3, or

can be restarted at a dose reduced by 5 mg/wk.

recommended is 15 mg/wk.

ver to grade 0–2 [13].

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0 927

secutive dose reductions are necessary, treatmentshould be stopped (Table 9). Treatment should bereinstated within a maximum of 4 wk or stoppeddefinitively. Daily doses should not exceed 50 mgnor be decreased below 25 mg. For temsirolimus,neutropenia (<1000/mm3) or thrombocytopenia(�75,000/mm3) requires treatment interruptionand reduction by 5 mg from the recommended doseof 25 mg [18]. The minimum recommended effectivedose consists of 15 mg (Table 9).

Sorafenib dose escalation, to 600 mg BID and up to800 BID, showed promise in progressors treated withregular doses (400 mg BID) [34]. Encouraging resultshave also been reported with sunitinib dose escala-tion [35].

It is noteworthy that the identified referencesneither provide the final follow-up guidelines nordemonstrated how to best recognize the complica-tions. As outlined above, the initial 2-wk follow-upand subsequent 4-wk follow-up intervals appearadequate. However, individual toxicity profiles mayoverride these recommendations. Patients withlower tolerance may require weekly visits. Con-versely, a large proportion of patients may be safelyfollowed every 6 wk or more, once they haveadapted to the medication.

Moreover, the cited references were unable toresolve the ongoing debate about the role ofurologists versus oncologists in the care of patientswith mRCC. In our opinion, knowledge of indica-tions and the ability to recognize and treat toxicitiesrepresent the prerequisites for delivery of kinaseinhibitors, regardless of primary specialty. A multi-disciplinary approach is key when treatment deci-sions are made and complex cases are handled [36].Close interactions between medical and surgicalspecialties provide the optimal mix between med-ical and surgical management of patients withmRCC. Appendix 1 lists the common side effectsin questionnaire format and Appendix 2 suggests asystematic approach to the care of the mostcommon side effects.

It is also important to bear in mind that thisreview is limited by the quality of the articles that itrelies on. For example, there might be importantdifferences in the reporting of side effects amongdifferent studies. This may contribute to differencesin the rate of specific side effects that are unrelatedto the treatment type. This type of bias is onlyavoidable if exactly the same design is used amongstudies. Standardized study design is not achievablebecause virtually all agent-specific studies weredesigned by competing pharmaceutical companies.The absence of head-to-head comparisons mayfurther confound the differences due to population

differences. For example, patients exposed totemsirolimus represented the patients with thepoorest prognosis (most advanced disease). Thissubgroup might have been the least resistant to thetoxic effects of systemic therapy due to extensivedisease burden. Unfortunately, population andmethodologic differences among the studies cannotbe controlled for in a retrospective fashion.

Our findings summarize the general toxicitytrends associated with sunitinib, sorafenib, andtemsirolimus. They indicate that the least amountof toxicity when all toxicity types are consideredmay be associated with the recommended dose ofsorafenib. Moreover, when the most life-threateningtoxicities, such as grade 3/4 neutropenia, is con-sidered temsirolimus represented the most favor-able agent. Unfortunately, it is difficult to objectivelyand validly state which of the agents is associatedwith the most favorable overall toxicity profiles.This difficulty is further compounded by populationdifferences and reporting differences in the quotedstudies.

Finally, it must be emphasized that efficacy andindications for treatment represent the foremostfactors that need to be considered in the selection ofone agent versus another. The current phase 3 dataprovide evidence that patients with mRCC inwhom previous therapy (eg, IFNa) failed derivedprogression-free survival from sorafenib and treat-ment-naıve patients derived progression-free survi-val benefit from sunitinib. Finally, poor-prognosispatients derived survival benefit from temsirolimus.These data represent valid selection criteria forchoosing between one versus another agent. In ouropinion, the toxicity information and the proposedmanagement guidelines should be applied as appro-priate after a context-specific choice of the mosteffective agent has been made. Treatment selectionshould never be made based on toxicity criteria alone.

Despite the limitations in the source of informa-tion regarding the toxicity of kinase inhibitors, ourreview fulfilled most of the criteria for scientificquality of a research review. Specifically, weprovided a detailed description of the searchmethod. Our search was comprehensive andincluded several databases. The inclusion criteriawere specified for each of the databases used.Selection bias was avoided, based on the use ofthese predefined criteria. The validity of eachmanuscript was confirmed based on its content(face validity) and by three independent reviewers(N.B., C.J., and P.K.). The findings of independentstudies were reported separately to avoid bias thatmay result from combining findings from severalstudies. Finally, conclusions were based on the rates

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0928

of specific toxicities and were free of interpretationbias. Therefore, the scientific criteria of our manu-script can be qualified as at least adequate.Despite the adherence to these criteria, our reviewis limited by the quality of the best availableliterature [6].

4. Conclusion

Sorafenib, sunitinib, and temsirolimus representeffective treatment options for patients with mRCC,but the drugs are not devoid of toxicity. Overall,sunitinib causes the most grade 3/4 side effects andsorafenib causes the fewest grade 3/4 side effects.Head-to-head trials that are based on patientswith the same entry level characteristics arerequired to validly compare safety profiles of allthree kinase inhibitors. We provide a comprehen-sive and systematic approach to the identificationand treatment of kinase inhibitor-related toxicities.Prevention, recognition, and prompt management

Appendix A

of side effects are of key importance and avoidunnecessary dose reductions, which may under-mine treatment efficacy. In future studies, treat-ment options will need to be adapted accordingto availability of agents, reimbursement patterns,as well as national and international treatmentguidelines.

Conflicts of interest

The authors have nothing to disclose.

Acknowledgments

Pierre I. Karakiewicz is partially supported by theUniversity of Montreal Health Center UrologyAssociates, Fonds de la Recherche en Sante duQuebec, the University of Montreal Department ofSurgery, and the University of Montreal HealthCenter (CHUM) Foundation.

Appendix B

e u r o p e a n u r o l o g y 5 3 ( 2 0 0 8 ) 9 1 7 – 9 3 0 929

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