A review of the patterns of docetaxel use for hormone-resistant prostate cancer at the Princess Margaret Hospital

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1 MEDICAL ONCOLOGY A review of the ptterns of docetxel use for hormone-resistnt prostte cncer t the Princess Mrgret Hospitl S.N. Chin MD,* L. Wng MSc, M. Moore MD,* nd S.S. Sridhr MD MSc* ABSTRACT Bckground Bsed on the t x 327 phse iii tril, docetxel-bsed chemotherpy is the stndrd first-line tretment for hormone-resistnt prostte cncer (h r p c); however, there is some heterogeneity in the use of this gent in routine clinicl prctice. The im of the present study ws to exmine the ptterns of docetxel use in routine clinicl prctice t our institution nd to compre them with docetxel use in the t x 327 clinicl tril. Methods We conducted retrospective chrt review of h r p c ptients treted with first-line docetxel between 2005 nd 2007 t the Princess Mrgret Hospitl. Results In the first-line setting, 88 ptients with h r p c received docetxel. The min resons for inititing docetxel were rising prostte-specific ntigen (ps, 98%) nd progressive symptoms (77%). The ps response rte ws 67%; medin time to response ws 1.5 months, nd durtion of response ws 6.8 months. Medin survivl ws 15.9 months (95% confidence intervl: 12.4 to 20.5 months). Ptients received medin of 7 cycles of tretment, nd the min toxicities were ftigue (35%) nd neuropthy (24%). Post docetxel, 36 ptients received second-line tretment with 22% response rte. Conclusions In routine clinicl prctice, h r p c ptients received docetxel minly becuse of symptomtic disese progression. Overll response rtes nd toxicities were comprble to those in the t x 327 tril. However, our ptients received medin of only 7 cycles of tretment versus the 9.5 dministered on tril, nd survivl ws slightly shorter in our single-institution study. A lrger prospective multicentre nlysis, including performnce sttus nd qulity-of-life prmeters, my be wrrnted to determine if docetxel performs s well in routine clinicl prctice s it does in the clinicl tril setting. KEY WORDS Prostte cncer, hormone refrctory, docetxel, chemotherpy 1. INTRODUCTION Prostte cncer is the most common cncer in men, with pproximtely 24,700 new cses dignosed nnully in Cnd 1. Ptients presenting with loclized prostte cncer re treted with curtive intent by surgery or rdition, but up to 30% will relpse. Tretment then involves ndrogen-bltion therpies, with initil response rtes of bout 80%. Those responses re temporry, however, nd ll ptients will eventully develop hormone-refrctory prostte cncer (h r p c). Hormone-refrctory prostte cncer is defined s rising ps despite ndrogen bltion. It cn mnifest s one or more of incresing ps, symptomtic progression, or rdiologic evidence of progressive disese when serum testosterone is t cstrte levels. This condition is incurble, with medin life expectncy of months. In the pst, systemic tretments for h r p c, such s mitoxntrone nd prednisone, offered pllitive benefit, but no survivl dvntge 2. Newer tretments with docetxel nd prednisone hve now been shown to offer both pllitive nd survivl benefits 3,4. Docetxel is member of the txne drug fmily, which cuses cell deth by inhibiting microtubule ctivity. On the bsis of two lrge rndomized clinicl trils (Southwest Oncology Group 9916 nd t x 327), 24 Copyright 2010 Multimed Inc.

2 Chin et l. docetxel is now considered the stndrd of cre in the mngement of h r p c. Southwest Oncology Group 9916 compred docetxel plus estrmustine with mitoxntrone plus prednisone nd showed medin overll survivl of 17.5 months in the docetxel rm nd 15.6 months in the mitoxntrone rm [hzrd rtio (h r): 0.80; 95% confidence intervl (c i): 0.67 to 0.77] 3. The t x 327 study compred two docetxel prednisone tretment rms (docetxel dministered weekly nd docetxel dministered every 21 dys) with mitoxntrone prednisone. The finl results showed tht docetxel every 21 dys hd h r for deth of 0.76 (95% c i: 0.62 to 0.94) with 2.4-month improvement in survivl (18.9 months vs months) compred with mitoxntrone 4. Updted survivl results confirmed tht benefit, with n improvement over mitoxntrone of 3.1 months (19.2 months vs months) in the docetxel-every-21-dys rm 5. On the bsis of those studies, the U.S. Food nd Drug Administrtion in My 2004 pproved the use of docetxel (75 mg/m 2 every 21 dys) nd prednisone s first-line therpy for metsttic h r p c. Helth Cnd grnted pprovl in My Docetxel prednisone cme into routine use t Princess Mrgret Hospitl in August Despite docetxel s pprovl for hrpc in the firstline setting, severl spects of its use remin heterogeneous nd uncler: for exmple, when to initite tretment, optiml durtion of tretment, nd pproprite tretment options fter docetxel filure. We used chrt review to specificlly exmine those fctors s they relte to the use of docetxel for the first-line tretment of h r p c in routine clinicl prctice. 2. METHODS After pprovl ws obtined from the institutionl reserch bord, we undertook retrospective chrt review of 88 ptients with h r p c treted with first-line docetxel chemotherpy from August 2005 to June 2007, with follow-up until Februry A list of eligible ptients ws obtined from the mbultory phrmcy, which mintins record of ll chemotherpy dministered ccording to drug nd disese site. The electronic ptient record (e p r) for ech of these ptients ws reviewed. Dt collection included demogrphics, indictions for tretment initition nd cesstion, dverse effects, nd number of cycles dministered. Adverse effects were ssessed from the e p rs, s recorded by the treting physicin t ech clinic visit. The cycles dministered were obtined from the mediction summry included in the e p r. We compred our ptient cohort with tht of the tx 327 study, recognizing tht, becuse of the retrospective nture of the review, we could not exctly mtch ll eligibility nd response criteri. Eligibility criteri for t x 327 required Krnofsky performnce sttus score of t lest 60% nd no prior tretment with chemotherpy except estrmustine. Our study found it difficult to ssess performnce sttus; however, 24 ptients who hd received prior chemotherpy were excluded from our nlysis. In t x 327, serum p s ws mesured every 3 weeks, nd response ws defined s reduction from bseline of t lest 50% mintined for t lest 3 weeks 6. Progression of ps ws defined s n increse from ndir of t lest 25% for men with no ps response or t lest 50% for ll others. Our study looked t more generl clinicl popultion, nd so the ps response criteri were less stringent. A response ws defined s t lest 50% reduction from bseline ps, nd progression ws defined s n increse of t lest 50% from ndir ps. Mny of the ptients ssessed in our study did not hve every-3-weeks ps redings vilble, nd responses were often not confirmed by repet ps 3 weeks lter. Our study did not ssess mesurble lesions, becuse these generlly were not meticulously recorded in the chrts of clinic ptients. Kpln Meier nlysis ws conducted for overll survivl nd medin survivl, nd n estimte of the confidence intervls ws mde. Finlly, we lso ssessed further lines of chemotherpy nd the responses thereto. 3. RESULTS Chrts were reviewed for the 112 ptients with h r p c who were treted with docetxel between August 2005 nd June The cut-off dte for nlysis ws Februry The 24 men who hd received prior chemotherpy with mitoxntrone were excluded from the review. Anlysis ws therefore limited to the 88 men who hd received no prior chemotherpy. Medin ge ws 71 yers, nd medin bseline ps ws 107 ng/ml. Tble i summrizes the ptient chrcteristics. 3.1 Initition of Docetxel Tretment In 86 ptients (98%), rising ps ws n indiction for strting chemotherpy tretment; in 36 ptients (41%), doubling time of 1 month or less ws n indiction. Symptoms were evident in 68 ptients (77%), nd 42 ptients (48%) hd rdiologic evidence of progressive disese. In 17 symptomtic ptients without rdiologic evidence of disese (19%), rising ps ws the only indiction for tretment (Tble i). 3.2 Response Chrcteristics The medin number of cycles dministered ws 7 (rnge: 1 12 cycles). A ps response ws documented in 59 ptients (67%). Medin time to ps response ws 1.5 months; to ps ndir, it ws 4.1 months. Medin durtion of response ws 6.8 months (rnge: months). Kpln Meier survivl nlysis showed tht medin durtion of survivl from first drug use ws 15.9 months (95% c i: months), nd 25

3 PATTERNS OF DOCETAXEL USE FOR HRPC AT PMH t b l e i Ptient chrcteristics nd indictions for initition of docetxel chemotherpy t Princess Mrgret Hospitl tble ii Tretment chrcteristics nd response to docetxel chemotherpy in 88 ptients t Princess Mrgret Hospitl Chrcteristic Vlue Chrcteristic Vlue Ptients (n) 88 Age Medin (yers) 71 Rnge (yers) yers [n (%)] 18 (20) Reson for inititing chemotherpy [n (%)] Rising prostte-specific ntigen (ps) 86 (98) Doubling time 1 month 36 (41) Doubling time 2 months 9 (10) Doubling time 3 months 7 (8) Doubling time unknown 34 (39) Rdiologic evidence of progressive disese 42 (48) Symptoms of progressive disese 68 (77) Rising ps only indiction b 17 (19) Symptoms t initition of chemotherpy [n (%)] 68 (77) ps t bseline (ng/ml) Medin 107 Rnge Follow-up (months) Medin 13.5 Rnge Sttus t lst follow-up [n (%)] Living 30 (34) Chemotherpy tretment with first-line docetxel Still undergoing tretment 3 (34) Totl exceeds 100% becuse more thn one reson my pply in ech cse. b Asymptomtic nd no rdiologic evidence. 1-yer survivl ws 0.63 (95% c i: ). Tble ii summrizes docetxel tretment chrcteristics nd response s mesured by ps level. 3.3 Adverse Effects Tble iii summrizes dverse events relted to chemotherpy. In our cohort, the most common dverse effects were ftigue (35%), sensory neuropthy (24%), peripherl edem (17%), nd nil chnges (14%). In the t x 327 tril, those dverse events occurred t the following frequencies: ftigue, 53%; sensory neuropthy, 30%; peripherl edem, 19%; nd nil chnges, 30%. In 9 ptients (10%), t lest 1 chemotherpy infusion hd to be delyed. The resons for dely included neutropeni (n = 4, 2 of whom hd febrile neutropeni episodes), nemi Response rte [n (%)] 59 (67) Time to ps response (months) Medin 1.5 Rnge Ndir ps (ng/ml) Medin 10.8 Rnge Time to ndir ps (months) Medin 4.1 Rnge Time to disese progression or durtion of response (months) Medin 6.8 Rnge Survivl (months) Medin 15.9 Rnge Cycles dministered (n) Medin 7 Rnge 1 12 One or more infusions delyed [n (%)] 9 (8) Use of g-c s f [n (%)] 1 (1) Resons for stopping tretment [n (%)] Mximum disese response 23 (26) Chemotherpy brek 19 (22) Disese progression 35 (40) Drug toxicity 15 (17) Missing dt 4 (5) Reduction in serum ps 50%. ps = prostte-specific ntigen; g-c s f = grnulocyte colony stimulting fctor. nd thrombocytopeni (n = 1), infection (n = 1), nd ftigue (n = 1); 2 ptients were delyed to llow tretment brek (reson not specified). 3.4 Second-Line Chemotherpy After progression, 36 of the 88 ptients (41%) went on to receive second-line chemotherpy fter medin chemotherpy-free intervl of 4 months (rnge: 1 10 months). Of these 36 ptients, 22% hd ps response. Tble iv summrizes the chrcteristics of, nd response to, second-line chemotherpy. Tble v summrizes post-docetxel tretments, which included mitoxntrone for 32 ptients (89%), who showed 26

4 Chin et l. t b l e iii Adverse effects during tretment of 88 ptients t Princess Mrgret Hospitl response rte of 19% nd medin durtion of response 4 months. The medin number of second-line cycles dministered ws 3.5. Crbopltin etoposide nd 5-flourourcil doxorubicin cyclophosphmide were used in 1 ptient ech, with ps response in both cses. 3.5 Third- nd Fourth-Line Therpy Nine percent of ptients (8/88) went on to receive third-line chemotherpy drugs: docetxel (n = 1), phse i study drug (n = 3), phse ii study drug (n = 1), nd the combintions cispltin etoposide (n = 2) nd 5-flourourcil doxorubicin cyclophosphmide (n = 1). One ptient received phse i drug in the fourth line. 4. DISCUSSION Adverse effect Frequency [n (% )] Ftigue 31 (35) Neuropthy 21 (24) Peripherl edem 15 (17) Nil chnges 12 (14) Gstrointestinl (nuse, vomiting, dirrhe) 9 (10) Tste chnges 7 (8) Febrile neutropeni 7 (8) Tering 5 (6) Alopeci 5 (6) Shortness of breth 5 (6) Neutropeni 4 (5) Mucositis 3 (3) Mylgi 3 (3) Thrombocytopeni 2 (2) Anemi 2 (2) Neutropenic sepsis 1 (1) Dizziness 1 (1) Allergic rection 0 Totl exceeds 100% becuse more thn one dverse effect my hve been experienced in ech cse. In this review, we ssessed the ptterns of first-line docetxel use for h r p c in routine clinicl prctice, nd we compred our findings with the pttern of use in the lndmrk t x 327 tril (Tble v i). Chrcteristics such s ge nd bseline ps were similr for both groups; however, not ll criteri were vilble for comprison. For exmple, most ptients in the 3-weekly docetxel rm of t x 327 hd Krnofsky performnce-sttus score of 80% or better, indicting reltively good t b l e iv Tretment nd response chrcteristics for 36 ptients who received second-line chemotherpy t Princess Mrgret Hospitl Bseline ps (ng/ml) Vrible Vlue Medin 141 Rnge Response rte [n (%)] 8 (22) Time to ps response (months) Medin 1.6 Rnge Ndir ps (ng/ml) Medin 48 Rnge 2 71 Time to ndir ps (months) Medin 2.3 Rnge Time to disese progression or durtion of response (months) Medin 4 Rnge 3 10 Cycles to disese progression (n) Medin 5 Rnge 1 7 Cycles dministered (n) Medin 3.5 Rnge 1 9 Second-line tretment still underwy [n (%)] 4 (11) Reson for stopping tretment [n (%)] Chemotherpy brek 3 (8) Progression of disese 24 (67) Adverse event 3 (8) Missing dt 6 (17) Subsequent third-line therpy [n (%)] 8 (22) Reduction in serum ps 50%. ps = prostte-specific ntigen. performnce sttus, but becuse performnce sttus is not meticulously documented in clinicl chrts, retrospective ssessment ws difficult. When to initite docetxel in h r p c ptients remins n importnt question 7. Our chrt review found tht symptomtic disese progression ws the most common reson for inititing docetxel; only 19% of 27

5 PATTERNS OF DOCETAXEL USE FOR HRPC AT PMH t b l e v Chemotherpy drugs nd responses in the second-line setting t Princess Mrgret Hospitl Chemotherpy Ptients [n (%)] Receiving Responding Second-line chemotherpy 36 8 (22) Drug Mitoxntrone 32 (89) 6 (19) Cytrbine 2 (5) 0 f c 1 (3) 1 Crbopltin etoposide 1 (3) 1 f c = 5-fluoroucil doxorubicin cyclophosphmide. t b l e v i Bseline, tretment, nd response chrcteristics of ptients treted t Princess Mrgret Hospitl (p m h ) nd in the t x 327 tril Age Chrcteristic Ptients p m h t x 327 b Medin (yers) Rnge (yers) yers [n (%)] Medin serum ps t bseline (ng/ml) Cycles (n) Medin Rnge % Reduction in serum ps Rte Durtion (months) Medin % Confidence intervl 2 to to 8.6 Survivl (months) Medin Rnge The 112 ptients from the present review. b From the docetxel-every-3-weeks rm: 335 ptients rndomized; 291 ptients evluble for ps response. ps = prostte-specific ntigen. ptients were treted becuse of rising ps lone. Becuse docetxel is not curtive tretment, witing for development of symptoms or rpid disese progression my be resonble pproch, nd in this window, ptients could be offered enrolment in clinicl trils. Another importnt question is the optiml durtion of docetxel tretment. In clinicl prctice, options include treting the ptient until toxicity becomes uncceptble, until disese progresses, or until few cycles beyond best response. The t x 327 study selected tretment durtion of 10 cycles, with 9.5 cycles ctully being dministered. In our review, the medin number of cycles dministered ws only 7. This key difference from the t x 327 study my hve relevnce, prticulrly when informing ptients bout the expected durtion of docetxel tretment. Severl resons might explin this difference: Criteri for discontinution my hve been more strict on tril. Tril ptients my hve been keen to continue tretment despite erly signs of progression. Clinic ptients my hve been more heterogeneous with respect to performnce sttus or comorbidities nd less ble to tolerte chemotherpy. A prospective study specificlly collecting performnce sttus nd qulity-of-life informtion would be required to directly ddress why fewer cycles were dministered. Despite receiving fewer cycles of chemotherpy, good response rte of 67% ws still chieved. This rte is higher thn the rte seen in t x 327, which is not surprising, becuse in the tril, confirmtory ps ws required something not routinely obtined in clinicl prctice 6. Ptients hd firly short medin time to ps response of 1.5 months, nd 4.1 months to ps ndir, indicting tht it is possible to know whether ptient is responding within 2 3 cycles of tretment. Although the response rte nd the durtion of response in our cohort were comprble to those of ptients in the t x 327 tril, medin survivl ws slightly shorter thn expected t 15.9 months compred with 18.9 months. Interestingly, study by Howrd et l. 8 lso reported tht, in terms of medin survivl, docetxel did not perform s well in routine prctice s it did in the clinicl tril setting. We hypothesize tht the lesser medin survivl my be ttributble to less-selected ptient popultion (whose members might hve been excluded from the clinicl tril becuse of medicl comorbidities such s crdic conditions) or to the dministrtion of fewer cycles of tretment. To dequtely explin this finding, lrger prospective study is required. The most common dverse events (ftigue, sensory neuropthy, peripherl edem, nd nil chnges) were similr to those seen in the t x 327 tril. Neutropeni ws recorded in 13% of ptients, with febrile neutropeni, which is more cliniclly significnt, described in 8% of our cohort (compred with 3% in t x 327). Neutropenic sepsis ws seen in only 1%, nd use of grnulocyte colony stimulting fctor in 1%. The fer of neutropenic complictions my be one of the fctors tht limits use of docetxel in h r p c, but these reltively low rtes of neutropenic sepsis re ressuring. Among our ptients, 17% discontinued docetxel becuse of dverse effects, compred with 28

6 Chin et l. 11% mong t x 327 ptients, suggesting tht, even in n unselected popultion, docetxel remins firly well-tolerted regimen. For ptients progressing on or fter docetxel, there is currently no ccepted stndrd second-line tretment for h r p c 9,10. In our study, 41% of ptients received second-line therpy fter medin chemotherpy-free period of 4 months; in the t x 327 study, 23% of ptients received second-line therpy. These numbers re significnt, considering tht the efficcy of second-line tretment is not well estblished nd tht this ptient popultion is frequently elderly nd fril. It does, however, reflect the incresing use of second-line therpy in h r p c nd the need for effective options 9. Our study provides further evidence for this trend, with 22% of ptients going on to receive third-line therpy. 5. CONCLUSIONS Bsed on the tx 327 rndomized tril, docetxelbsed chemotherpy is the stndrd first-line tretment for ptients with h r p c; however, there is some heterogeneity in its use in routine clinicl prctice, which my vry from tht in the t x 327 tril. We found tht most h r p c ptients received docetxel becuse of combintion of symptoms nd disese progression. The medin time to response ws 1.5 months (2 3 cycles), nd the durtion of response ws 6.8 months. Overll response rtes nd toxicities were comprble to those in the t x 327 tril, except tht our ptients received medin of only 7 cycles of tretment versus 9.5 on tril, nd tht survivl ws slightly shorter in our single-institution study. A lrger prospective multicentre nlysis, including performnce sttus nd qulity-of-life prmeters, my be wrrnted to determine whether docetxel performs s well in routine clinicl prctice s it does in the clinicl tril setting, nd to better understnd postdocetxel tretment pproches nd response rtes. 6. CONFLICT OF INTEREST DISCLOSURE The uthors declre tht no finncil conflict of interest exists. 7. ACKNOWLEDGMENTS The uthors thnk Anthe Lu (Deprtment of Biosttistics, Princess Mrgret Hospitl, Toronto, ON). 8. REFERENCES 1. Cndin Cncer Society nd the Ntionl Cncer Institute of Cnd. Cndin Cncer Sttistics Toronto: Cndin Cncer Society; [Avilble online t: cncer/cncer sttistics/~/medi/ccs/cnd wide/files List/English files heding/pdf not in publictions section/cndin Cncer Society Sttistics PDF 2008_ shx; cited Februry 14, 2010] 2. Tnnock IF, Osob D, Stockler MR, et l. Chemotherpy with mitoxntrone plus prednisone or prednisone lone for symptomtic hormone-resistnt prostte cncer: Cndin rndomized tril with pllitive end points. J Clin Oncol 1996;14: Petrylk DP, Tngen CM, Hussin MH, et l. Docetxel nd estrmustine compred with mitoxntrone nd prednisone for dvnced refrctory prostte cncer. N Engl J Med 2004;351: Tnnock IF, de Wit R, Berry WR, et l. on behlf of the t x 327 Investigtors. Docetxel plus prednisone or mitoxntrone plus prednisone for dvnced prostte cncer. N Engl J Med 2004;351: Berthold DR, Pond GR, Sobn F, de Wit R, Eisenberger M, Tnnock IF. Docetxel plus prednisone or mitoxntrone plus prednisone for dvnced prostte cncer: updted survivl in the t x 327 study. J Clin Oncol 2008;26: Bubley GJ, Crducci M, Dhut W, et l. Eligibility nd response guidelines for phse ii clinicl trils in ndrogen-independent prostte cncer: recommendtions from the Prostte-Specific Antigen Working Group. J Clin Oncol 1999;17: Hmberg P, Verhgen PC, de Wit R. When to strt cytotoxic therpy in symptomtic ptients with hormone refrctory prostte cncer? Eur J Cncer 2008;44: Howrd DN, Chmbers C, Cusno F. Efficcy vs. effectiveness docetxel nd prednisone in hormone refrctory prostte cncer. J Oncol Phrm Prct 2008;14: Berthold DR, Pond GR, de Wit R, Eisenberger M, Tnnock IF on behlf of the t x 327 Investigtors. Survivl nd ps response of ptients in the t x 327 study who crossed over to receive docetxel fter mitoxntrone or vice vers. Ann Oncol 2008;19: Sternberg CN, Petrylk D, Witjes F, et l. Strpltin (s) demonstrtes significnt clinicl benefits for the tretment of ptients with h r p c: results of rndomized phse iii tril (bstrct 5019). Proc Am Soc Clin Oncol 2007;25:. [Avilble online t: Abstrcts?&vmview=bst_detil_view&confID=47&bstr ctid=31837; cited Februry 10, 2010] Correspondence to: Srikl Sridhr, University of Toronto, Princess Mrgret Hospitl, 610 University Avenue, Suite 5-222, Toronto, Ontrio M5G 2M9. E-mil: srikl.sridhr@uhn.on.c * Division of Medicl Oncology nd Hemtology, Princess Mrgret Hospitl, Toronto, ON. Deprtment of Biosttistics, Princess Mrgret Hospitl, Toronto, ON. 29