Olanzapine for the prophylaxis and rescue of chemotherapyinduced nausea and vomiting (CINV): a retrospective study

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1 Originl Article Olnzpine for the prophylxis nd rescue of chemotherpyinduced nuse nd vomiting (CINV): retrospective study Leonrd Chiu, Nichols Chiu, Ronld Chow, Liying Zhng, Mrk Psetk, Jordn Stinson, Brenne Lechner, Ntlie Pulenzs, Sunil Verm, Edwrd Chow, Crlo DeAngelis Sunnybrook Odette Cncer Centre, University of Toronto, Toronto, ON, Cnd Contributions: (I) Conception nd design: L Chiu, E Chow, C DeAngelis; (II) Administrtive support: L Chiu, N Chiu; (III) Provision of study mterils or ptients: C DeAngelis, E Chow; (IV) Collection nd ssembly of dt: L Chiu, L Zhng; (V) Dt nlysis nd interprettion: L Chiu, L Zhng; (VI) Mnuscript writing: All uthors; (VII) Finl pprovl of mnuscript: All uthors. Correspondence to: Dr. Edwrd Chow, MBBS, MSc, PhD, FRCPC. Deprtment of Rdition Oncology, Odette Cncer Centre, Sunnybrook Helth Sciences Centre, 2075 Byview Avenue Toronto, Ontrio M4N 3M5, Cnd. Emil: edwrd.chow@sunnybrook.c. Bckground: While the efficcy of olnzpine in the prophylxis of chemotherpy-induced nuse nd vomiting (CINV) hs been documented, the literture on the use of olnzpine s rescue mediction for brekthrough CINV hs been scrce. The following study retrospectively evluted the sfety nd efficcy of olnzpine for the tretment of brekthrough CINV. The efficcy nd sfety of olnzpine in the prophylctic setting ws lso exmined in smller cohort. Methods: Electronic medicl records of dult ptients ged >17 yers receiving prescription for olnzpine from the Odette Cncer Centre Phrmcy t Sunnybrook Hospitl between Jnury 2013 nd June 2015 were reviewed retrospectively. Inclusion criteri required receiving one or more doses of olnzpine for the rescue or prophylxis of CINV nd documenttion of the outcome. Results: A totl of 154 ptients nd 193 tretment cycles were included in the brekthrough setting, while totl of 16 ptients nd 20 tretment cycles were included in the prophylxis setting. In the brekthrough setting, 88% of cses experienced improved nuse, while 21% of cses reported improved vomiting. In the prophylctic setting, 100% of cses experienced improved nuse, while 65% chieved improved vomiting. A totl of 43% of cses in the brekthrough setting nd 65% of cses in the prophylctic setting experienced sedtion. Conclusions: Olnzpine is effective in improving CINV in both the prophylctic nd brekthrough settings. The sfety, efficcy, nd pproprite dosge of olnzpine for the rescue of brekthrough CINV should be prospectively evluted in rndomized controlled tril (RCT). Keywords: Olnzpine; chemotherpy-induced nuse nd vomiting (CINV); brekthrough emesis; prophylxis; efficcy Submitted Dec 31, Accepted for publiction Mr 18, doi: /pm View this rticle t: Introduction Chemotherpy-induced nuse nd vomiting (CINV) is well-documented dverse effect for ptients undergoing chemotherpy tretment (1-5). Left untreted, CINV my result in serious complictions, thus potentilly compromising outcome if dose reduction or discontinution of therpy is required (6). At present, current ntiemetic guidelines recommend tht three-drug combintion of 5-HT 3 ntgonist, dexmethsone, nd neurokinin 1 (NK-1) inhibitors be used in the prophylxis of cute CINV in the highly emetogenic chemotherpy (HEC) settings, while two-drug combintion of plonosetron nd dexmethsone is recommended in the modertely emetogenic chemotherpy settings (MEC) (7,8). For

2 Annls of Pllitive Medicine, Vol 5, No 3 July 2016 delyed CINV, combintion of dexmethsone nd prepitnt is recommended in the HEC settings, while dexmethsone or prepitnt cn be used in MEC settings (7,8). However, despite prophylctic tretment, CINV my nevertheless rise. Filure to control CINV with the id of prophylctic ntiemetics is defined s brekthrough CINV (8), nd t present, mny medictions re recommended by clinicl guidelines but no specific gent for this type of CINV is preferred (8). Olnzpine is n ntipsychotic mediction with cliniclly observed ntiemetic effects (9). The Food nd Drug Administrtion (FDA) pproved drug blocks multiple neurotrnsmitters: dopmine t D1, D2, D3 nd D4 brin receptors, serotonin t 5-HT 2, 5-HT 2c, 5-HT 3, nd 5-HT 6 receptors, ctecholmines t lph-1 drenergic receptors, cetylcholine t muscrinic receptors, nd histmine t H1 receptors (10). Since 2000, when cse report first documented the efficcy of olnzpine in relieving the chronic nuse of leukemi ptient (11), severl phse I nd II studies (12-18), other rndomized controlled trils (RCTs) (19-23), nd recent systemtic reviews nd met-nlyses (24,25), hve been published which document the effective use of olnzpine s prophylctic ntiemetic in controlling CINV. However, only two studies hve documented the use of olnzpine for the rescue of brekthrough CINV (26,27). With the reltively few number of studies in the literture documenting olnzpine in the brekthrough setting, the primry objective of this study ws to determine the efficcy nd sfety of olnzpine when given s rescue mediction to ptients who experience brekthrough CINV. The secondry objective ws to determine the efficcy nd sfety of olnzpine s prophylxis tretment of CINV. Methods Study design nd ptient selection Following pprovl from the Toronto Acdemic Helth Sciences Network (TAHSN) Reserch Ethics Bord, electronic medicl records of dult ptients ged >17 yers receiving prescription for olnzpine from the Odette Cncer Centre Phrmcy t Sunnybrook Hospitl between Jnury 2013 nd June 2015 were reviewed retrospectively. Inclusion criteri required receiving one or more doses of olnzpine for the rescue or prophylxis of CINV nd documenttion of the outcome. In the prophylctic setting, olnzpine ws dministered for the first three dys fter chemotherpy, strting on the dy of chemotherpy, twice 173 dy. In the brekthrough setting, ech ptient must hve received some form of stndrd prophylctic ntiemetic before the dministrtion of first-line rescue ntiemetic. First-line rescue ntiemetic is defined s the subsequent ntiemetic mediction given fter clinicl filure of prophylctic ntiemetics. Olnzpine ws dministered s the first-line rescue ntiemetic for the mjority of ptients. Other ptients my hve used prochlorperzine s firstline rescue mediction, but switched to olnzpine becuse of clinicl filure or the mediction induced side effects severe enough to wrrnt discontinution by the ptient. Olnzpine dministrtion for brekthrough CINV must hve been given fter clinicl filure of prophylctic ntiemetics nd/or filure of non-olnzpine contining first-line rescue. In the rescue setting, ech mediction ws lwys dministered seprtely nd sequentilly. Ptients were excluded if olnzpine ws used before chemotherpy. In both the rescue nd prophylctic settings, the primry outcome mesure ws the percentge of ptients who took olnzpine nd found it to improve nuse or vomiting. In both the nuse nd vomiting endpoints, filure ws defined s the ptient indicting CINV to be sme or worse upon olnzpine use. Secondry outcome mesures included the percentge of ptients who took olnzpine nd developed side effects. Ptients were strtified by chemotherpy emetogenicity level nd type, number of prophylctic ntiemetics received, dosge of olnzpine used, tretment intent, s well s by risk fctors such s ge, gender, nd lcohol consumption. Chemotherpy emetogenicity levels were seprted into high, medium nd low potentils, prophylctic nti-emetics divided into groups of single, double, or triple gents, dosge of olnzpine ws exmined in either 2.5 or 5 mg, nd tretment intent into djuvnt, neodjuvnt, pllitive, or curtive. Risk fctors were seprted into ge younger thn 55 versus ge 55 yers or older nd lcohol use less thn 5 drinks/week versus use of 5 drinks/week or more. Assessment procedures At the Odette Cncer Centre, ptients re followed up with phone cll by phrmcist or phrmcy reserch ssistnt 72 hours fter every cycle of chemotherpy. Any outcomes of CINV for the initil cycle fter this 72-hour period would be mde in the next tretment cycle in the hospitl or within the 72 hour period follow-up in the next cycle. An ssessment of CINV ws documented in the ptient s electronic medicl records. In both the prophylctic nd

3 174 Chiu et l. Olnzpine for prophylxis nd rescue of CINV: retrospective study Tble 1 Ptient demogrphics nd bseline risk fctors Chrcteristic Age (yers) Medin 51 Rnge Gender brekthrough setting, ptients were sked whether they experienced improved, worse, or sme CINV fter tking olnzpine. Sttisticl methods Totl (n=170, 100%) No. % Femle Mle Primry cncer site Brest Gstrointestinl H/N Gynecology Hemtology Lung Genitourinry Other Bseline risk fctors Age (yers) > Alcohol use >5 drinks/week No Yes Any cffeine use No Yes Any tobcco use No Yes Descriptive nlysis ws conducted using medin nd rnges for continuous vribles nd proportions for ctegoricl vribles. To compre olnzpine outcomes on clinicl fctors, Wilcoxon rnk-sum (for two ctegories of olnzpine outcomes) or Kruskl-Wllis (for >2 ctegories of olnzpine outcomes) nonprmetric test ws used for continuous vribles nd Chi-squred test or Fisher exct test ws used s pproprite for ctegoricl vribles. Twosided P vlue <0.05 ws considered sttisticlly significnt. All nlyses were performed by Sttisticl Anlysis Softwre (SAS version 9.4 for Windows). Results Ptient chrcteristics A totl of 170 ptients nd 213 tretment cycles were included: 142 women nd 28 men with men ge of 50.9 yers (rnge, 19 77) (Tble 1). The most common primry cncer site ws brest cncer (n=97, 57%) (Tble 1). Other demogrphic informtion, including bseline risk fctors such s lcohol nd cffeine consumption, cn be found in Tble 1. Efficcy nd sfety prmeters in the brekthrough setting A totl of 154 ptients nd 193 tretment cycles were included in the brekthrough setting (Tble 2). Tble 3 documents the proportion of ptients with different olnzpine outcomes for nuse nd vomiting in the brekthrough setting. Subgroup nlysis reveled tht the effectiveness of olnzpine for brekthrough CINV ws not dependent on the cycle it strts on (P=0.3), nor ws it dependent on the emetogenic potentil (P=0.1), the tretment intent (P=0.2), or the type (P=0.3) of the chemotherpy regimen. In ddition, there is no significnt reltionship between hving single, double, or triple prophylctic ntiemetic regimen nd subsequent olnzpine outcomes (P=0.4). In ddition, there ws no significnt difference on side effects or outcomes between the use of 2.5 or 5 mg dose of olnzpine. No significnt reltionship between bseline demogrphics nd different olnzpine outcomes were found either. Efficcy nd sfety prmeters in the prophylctic setting A totl of 16 ptients nd 20 tretment cycles were included in the prophylxis setting (Tble 4). In ll 16 ptients nd 20 cses, olnzpine use ws indicted by ptients to hve improved nuse in the prophylctic setting, while

4 Annls of Pllitive Medicine, Vol 5, No 3 July Tble 2 Tretment cycles nd ntiemetics in the brekthrough setting Chrcteristic Number of tretment cycles with olnzpine use Medin 1 Rnge 1 12 Emetogenic potentil (n =193, 100%) No. % High High/low Low Medium Olnzpine dose 2.5 mg mg Tretment intent Adjuvnt Neodjuvnt Pllitive Curtive Prophylctic nti-emetics Single (dexmethsome or 5-HT 3 ntgonist) Double (5-HT 3 ntgonist nd prepitnt) Triple (5-HT 3 ntgonist, dexmethsome, prepitnt) Type of rescue medictions Olnzpine Prochlorperzine, olnzpine Olnzpine, prochlorperzine Olnzpine, domperidone Prochlorperzine, domperidone, olnzpine Prochlorperzine, olnzpine, metocloprmide 6 3.1, tretment cycles. 7 cses (35%) chieved improved vomiting (Tble 3). A totl of 65% of the cses indicted the feeling of sedtion fter olnzpine use, while 35% of the cses indicted experiencing constiption (Tble 5). As in the brekthrough setting, subgroup nlysis reveled Tble 3 Proportion of ptients with different outcomes upon use of olnzpine for brekthrough CINV or the prevention of CINV Olnzpine outcomes tht the effectiveness of olnzpine for the prevention of CINV ws not dependent on the cycle it strts on (P=0.98), the emetogenic potentil (P=0.6), the tretment intent (P=0.9), or the type (P=0.4) of the chemotherpy regimen. Moreover, there ws no significnt reltionship between hving single, double, or triple prophylctic ntiemetic regimen nd subsequent olnzpine outcomes (P=0.5). Although there ws no significnt difference between the use of 2.5 or 5 mg dose of olnzpine with respect to the ntiemetic outcome or the incidence of constiption, there ws significnt difference between the two doses with regrds to the incidence of sedtion. The use of 5 mg olnzpine dose ws ssocited with significntly higher proportions of sedtion compred to 2.5 mg dose (P=0.03). Discussion Rescue setting (n=193, 100%) Prophylxis setting (n=20, 100%) No. % No. % b Improved nuse Improved vomiting Filure nuse c Filure vomiting d , totl number of chemotherpy cycles [193] is used s the denomintor for clculting the proportions in this setting; b, totl number of chemotherpy cycles [20] is used s the denomintor for clculting the proportions in this setting; c, filure nuse is defined s worse or sme nuse level despite the use of olnzpine; d, filure vomiting is defined s worse or mount of vomiting despite the use of olnzpine. CINV, chemotherpy-induced nuse nd vomiting. The efficcy of olnzpine in the prophylxis of CINV hs been documented (12-23). However, literture on the use of olnzpine s rescue mediction for brekthrough CINV hs been scrce, with only two studies investigting the use of olnzpine for this purpose (26,27). As such, we focus on the two rticles by Chnthwong et l. (26) nd Nvri et l. (27) s frmework for our discussion. The current study retrospectively detils the efficcy nd sfety of olnzpine for the tretment of brekthrough CINV. It is the lrgest study of this nture to dte, with totl of 154 ptients nd 193 tretment cycles in the

5 176 Chiu et l. Olnzpine for prophylxis nd rescue of CINV: retrospective study Tble 4 Tretment cycles nd ntiemetics in the prophylctic setting Chrcteristic Number of tretment cycles with olnzpine use Medin 1 Rnge 1 10 Emetogenic potentil (n =20, 100%) No. % High Low Medium Olnzpine dose 2.5 mg mg Tretment intent Adjuvnt Neodjuvnt Pllitive Curtive Prophylctic nti-emetics Double (5-HT 3 ntgonist nd prepitnt) Triple (5-HT 3 ntgonist, dexmethsome, prepitnt) Olnzpine , tretment cycles. brekthrough setting. With pproximtely 88% of cses indicting tht olnzpine improved brekthrough nuse, the proportion in this study is, s expected, higher thn the 68% of ptients in the Nvri study tht indicted no nuse (27), nd the complete response in nuse rte of 50% reported by Chnthwong et l. (26). The proportion of improved vomiting (22%) in our study is considerbly lower thn the no emesis (70%) nd complete response in emesis (60.9%) rtes reported by Nvri et l. nd Chnthwong et l., respectively. In the Chnthwong study, complete response in nuse ws s no emetic episodes, no rescue therpy nd no nuse, while the complete response in emesis ws defined s no emetic episodes nd no rescue therpy. It should be noted tht the doses used by Nvri et l. nd Chnthwong et l. were 10 mg dily nd 5 mg twice dy, respectively. Given tht the methodology used in this study is different from the ones used by Chnthwong et l. nd Nvri et l., the results re not comprble. Specificlly, the study by Chnthwong et l. is phse II prospective open lbel clinicl tril tht mesured the rtes of complete response for brekthrough emesis, retching nd nuse using the Index of Nuse, Vomiting nd Retching: INVR tool. The study by Nvri et l. is rndomized phse III tril tht mesured rtes of complete response using visul nlog scle from 0 to 10, with 0 indicting no nuse nd 10 indicting mximl level of nuse. On the other hnd, the retrospective nture of this study nd the limited informtion vilble from the electronic medicl records limited this study s bility to report on the more commonly used endpoints in ntiemetic Tble 5 Proportion of ptients who took olnzpine nd developed certin side-effects Side effect Rescue setting (n=193, 100%) Prophylxis setting (n=20, 100%) No. % No. % b Sedtion Sedtion with continution of olnzpine Sedtion with discontinution of olnzpine Constiption Mild, constiption, no mediction prescribed Severe constiption with prescribed medictions , totl number of chemotherpy cycles [193] is used s the denomintor for clculting the proportions in this setting; b, totl number of chemotherpy cycles [20] is used s the denomintor for clculting the proportions in this setting.

6 Annls of Pllitive Medicine, Vol 5, No 3 July 2016 clinicl trils such s no emesis nd no nuse. Moreover, the proportions of improvement for nuse nd vomiting my be under-estimted. As documenttion is predicted on phone-cll follow-up, improvement of CINV my not lwys be communicted by ptients. This study is the first to report the proportion of ptients tht experienced side effects in the brekthrough setting, with 42% of cses experiencing sedtion nd 32% experiencing constiption. With 65% of ptients experiencing sedtion in the prophylctic setting, this study reports the incidence of sedtion to be lower thn the 73% indicted by study by Tn et l. (19). It should be noted tht in our study, olnzpine ws dministered in smller 2.5 or 5 mg doses thn the 10 mg dose used by Tn et l. Our findings tht 2.5 mg dose of olnzpine in the prophylctic setting is ssocited with similr CINV outcomes, but smller incidence of sedtion thn 5 mg dose further support the recommendtion of dosge reduction. While it is well known tht the emetogenicity of chemotherpy dministered, gender, ge, s well s history of low prior lcohol intke, cn ffect ptients risk fctors for CINV (28), it is reltively unknown whether the before mentioned bseline risk fctors cn ffect the efficcy of olnzpine use. Our study found no significnt differences between ptients with bseline risk fctors nd those without, in both the prophylxis nd brekthrough settings. Our study lso found tht the effectiveness of olnzpine in both the prophylxis nd brekthrough settings is not dependent on the cycle it strted on. This study is limited by its retrospective design. Specificlly, informtion on the intensity of brekthrough nuse or the number of brekthrough vomiting episodes before nd fter the use of olnzpine ws not recorded, nd thus, more stndrd definitions of filure in the tretment of brekthrough CINV could not be used. In ddition, ptients received different combintions of prophylctic nti-emetics tht my hve confounded the efficcy of olnzpine for brekthrough CINV. However, mesures hve been tken to minimize its limittions. For exmple, our nlysis showed tht there ws no significnt difference between receiving single gent prophylctic nti-emetic (dexmethsone or 5-HT 3 ntgonist), double gent ntiemetic ( 5-HT 3 ntgonist coupled with NK-1 inhibitor), or triple gent nti-emetic ( 5-HT 3 ntgonist, dexmethsone, nd NK-1 inhibitor) with respect to the efficcy of olnzpine s rescue mediction for brekthrough CINV. In conclusion, this study found olnzpine to be effective in improving CINV in both the prophylctic nd 177 brekthrough settings. The incidence of sedtion in both settings ws found to be lower thn the only other reported incidence of sedtion of 73%, though it should be noted tht our study used lower doses. Given the similr benefit fforded by 2.5 nd 5 mg dose, we recommend the use of lower doses of olnzpine in both the prophylctic nd brekthrough settings. The sfety, efficcy, nd pproprite dosge of olnzpine for the rescue of brekthrough CINV should be prospectively evluted in RCT. Acknowledgements We thnk the generous support of Brtty Fmily Fund, Michel nd Kryn Goldstein Cncer Reserch Fund, Joey nd Mry Furfri Cncer Reserch Fund, Pulenzs Cncer Reserch Fund, Joseph nd Silvn Melr Cncer Reserch Fund, nd Ofeli Cncer Reserch Fund. Footnote Conflicts of Interest: The uthors hve no conflicts of interest to declre. Ethicl Sttement: The study ws pproved by the Toronto Acdemic Helth Sciences Network (TAHSN) Reserch Ethics Bord. References 1. Cotes A, Abrhm S, Kye SB, et l. On the receiving end--ptient perception of the side-effects of cncer chemotherpy. Eur J Cncer Clin Oncol 1983;19: Lszlo J. Nuse nd vomiting s mjor complictions of cncer chemotherpy. Drugs 1983;25 Suppl 1: Levine AM, Richrdson JL, Mrks G, et l. Complince with orl drug therpy in ptients with hemtologic mlignncy. J Clin Oncol 1987;5: Lindley CM, Bernrd S, Fields SM. Incidence nd durtion of chemotherpy-induced nuse nd vomiting in the outptient oncology popultion. J Clin Oncol 1989;7: Richrdson JL, Mrks G, Levine A. The influence of symptoms of disese nd side effects of tretment on complince with cncer therpy. J Clin Oncol 1988;6: Osob D, Zee B, Wrr D, et l. Effect of postchemotherpy nuse nd vomiting on helth-relted qulity of life. The Qulity of Life nd Symptom Control Committees of the Ntionl Cncer Institute of Cnd Clinicl Trils Group.

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