University of Texas Health Science Center, San Antonio, San Antonio, Texas, USA

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1 Lung Cncer Chemotherpy Given Ner the End of Life by Community Oncologists for Advnced Non-Smll Cell Lung Cncer Jose R. Murillo, Jr., Jim Koeller b,c Methodist Hospitl, Houston, Texs, USA; b University of Texs t Austin, Austin, Texs, USA; c University of Texs Helth Science Center, Sn Antonio, Sn Antonio, Texs, USA Abstrct Purpose. To chrcterize the chemotherpy given ner the end of life to dvnced non-smll cell lung cncer (NSCLC) ptients treted in the community oncology setting using medicl records dtbse. Methods. We conducted retrospective chrt review of expired dvnced (stge IIIb/IV) NSCLC ptients treted with chemotherpy. Ptients who initited chemotherpy in were eligible. Ptient demogrphics, ll chemotherpy including dose nd schedule, nd disese-relted events were collected. Results. We report dt from 10 community prctices including 417 ptients treted for dvnced NSCLC in The men ge ws 67 yers (medin, 62 yers) nd 54% were mle. Forty percent of ptients were >69 yers of ge nd 35% hd n Estern Coopertive Oncology Group performnce sttus score of 2. First-line chemotherpy included combintion therpy in 84% of ptients. Second-line therpy ws given to 56% of ptients. Twenty-six percent of ptients received third-line therpy, while 10% received fourth-line therpy nd 5% received fifth-line therpy or greter. Ptients received men of 6.1 cycles of chemotherpy. For ptients receiving chemotherpy t the time of deth, the men line of therpy being given ws second line. Chemotherpy ws given within 1 month nd 2 weeks of deth to 43% nd 20% of ptients, respectively. Conclusion. The vilbility of new chemotherpeutic gents hs cused subsequent increse in the length of time ptients re receiving chemotherpy with dvnced NSCLC. This would suggest n incresed use of chemotherpy ner the end of life, which ws identified in this study. The Oncologist 2006;11: Introduction Over the pst 15 yers, severl new tretment options hve become vilble for the mngement of dvnced (stge IIIb/IV) non-smll cell lung cncer (NSCLC). These dditionl ctive gents (e.g., crbopltin, pclitxel, gemcitbine, docetxel, vinorelbine, gefitinib, erlotinib, pemetrexed) hve now mde first-, second-, nd even third-line tretment of dvnced NSCLC more commonplce. Both the Americn Society of Clinicl Oncology s updted 2003 NSCLC tretment guideline nd the Ntionl Comprehensive Cncer Network (NCCN) NSCLC clinicl prctice guideline version cknowledge first-, second-, nd third-line tretments of dvnced NSCLC [1, 2]. However, even with these tretment dvnces, survivl hs incrementlly incresed by only months [3 14]. This hs the potentil for blurring the lines between receiving wht could pper to be cceptble chemotherpy nd ggressively getting tretment too close to the time of deth. There hve been few publictions, most in bstrct form, tht hve quntittively described end-of-life chemotherpy strtegies for cncer ptients. In 2001, Emnuel et l. [15] reported the results of review of over 7,900 Medicre cncer ptients, in which 26% of ptients received chemotherpy in the lst 3 months of life, nd 14% received Correspondence: Jim Koeller, M.S., University of Texs Helth Science Center, Medicine MSC-6220, 7703 Floyd Curl Drive, Sn Antonio, Texs , USA. Telephone: ; Fx: ; e-mil: koeller@uthscs.edu Received Mrch 28, 2006; ccepted for publiction September 1, AlphMed Press /2006/$20.00/0 doi: /theoncologist The Oncologist 2006;11:

2 1096 End-of-Life Chemotherpy for NSCLC chemotherpy within the lst 1 month of life. With respect to lung cncer ptients, 36%, 21%, nd 11% received chemotherpy within 12, 3, nd 1 months of deth, respectively [15]. In 2003, Argon-Ching et l. [16] reported the results from single-institution study, in which 144 ptients (27% lung cncer) received chemotherpy t the end of life. Of these, 26% received chemotherpy within 1 month of deth nd 43% received chemotherpy within 6 months of deth. In 2002, Giorgi et l. [17] reported review of clinicl dt for 193 ptients (30% NSCLC) receiving end-of-life chemotherpy, of which 66% received tretment within 3 months of deth nd 33% received chemotherpy within 1 month of deth. Agin, no specifics relted to the chemotherpeutic gents given or the line of therpy were provided. Finlly, in 2004 Erle et l. [18] described results of Medicre/Surveillnce, Epidemiology, nd End Results (SEER) dtbse review of 8,155 chemotherpy-treted cncer ptients in (53% lung cncer) who were over the ge of 64. The uthors concluded tht end-of-life chemotherpy usge ptterns hve become more ggressive, with lmost 16% of ptients receiving chemotherpy within 14 dys of deth. Agin, there were no detils provided describing the specific chemotherpy nd line of therpy given. Historiclly, mny hve ctegorized chemotherpy ner the end of life s ggressive nd typiclly unnecessry. However, most prctitioners will counter tht it cn be difficult, if not impossible, to determine when the life of ptient with dvnced disese will ctully end. Current reports of this prctice pttern clerly provide vluble informtion; however, they re not without limittion. As most of the dt hve come in bstrct form, they lck specific informtion regrding both the types nd lines of chemotherpy used, nd most of the reports involved ptients with vrious cncer types. Furthermore, the mjority of the informtion vilble is decde old nd lcks ptient nd tretment specifics, with the exception of the Giorgi et l. [17] report. Tht report provides more comprehensive pproch, including detils on chemotherpy regimen nd line of tretment in contemporry cohort of dvnced NSCLC ptients in community oncology setting. Methodology This retrospective chrt review, institutionl review bord pproved study evluted dvnced (stge IIIb/IV) NSCLC ptients treted with chemotherpy in multiple community oncology prctices in This is n observtionl study only. In rel-world terms, this dtbse cptured how the community oncologist pproches the tretment of NSCLC on dy-to-dy bsis. This study did not evlute the physicin ptient reltionship nd the specifics relted to decisions mde prior to ech line of therpy. Dt cpture ws crried out by single, four-member reserch tem. A cross-section of community prctices from cross the country ws sought. Clinics needed to hve t lest three prcticing medicl oncologists nd be willing nd ble to identify nd locte the chrts of lung cncer ptients. Inclusion criteri included ptients with dignosis of dvnced NSCLC (stge IIIb, cliniclly ny T, N3, M0 or T4, ny N, M0; stge IV, cliniclly metsttic disese) who received chemotherpy s prt of their primry tretment, nd expired. Dt were cptured on stndrdized form nd included: () ptient chrcteristics (ge, gender, height, weight, performnce sttus [PS] score t the strt of chemotherpy, stge of disese, prior chemotherpy tretment, prior surgery, nd prior rdition therpy); (b) tretment (ll chemotherpy gents, dose, nd schedule); nd (c) disese-relted events (progression of disese, stble disese, therpy completed, therpy chnged, nd the dte of deth). Becuse of the nture of retrospective chrt review nd the inbility to ensure ccurcy nd consistency cross ll ptients, cuse of deth ws not cptured. All dt from the sheets were then entered into computerized dtbse with double check ginst the originl form for entry ccurcy. Results From Mrch to November 2003, 10 community oncology clinics from cross the U.S. (e.g., Nevd, Louisin, Indin, Illinois, Kentucky, Mine, Connecticut, nd Florid) were visited for dt cpture. Four hundred seventeen expired ptients comprised the dtbse. Dt were cptured from the time of first chemotherpy tretment (with or without rdition therpy) to the time of deth. Twentytwo percent of ptients received chemotherpy in 2003, 36% received chemotherpy in 2002, 27% received chemotherpy in 2001, nd 15% received chemotherpy in Ptient demogrphics cn be found in Tble 1. Fiftyfour percent of ptients were men. The men ge ws 67 yers; however, 40% of ptients were >69 yers of ge. The mjority of ptients (73%) hd stge IV disese, nd 65% of ptients hd n Estern Coopertive Oncology Group PS score t the initition of tretment of 0 1. Of the 35% of ptients who hd PS score 2, only 14 (3%) hd PS score of 3 t the strt of therpy. Ten percent of ptients received prior surgery, 10% received prior chemotherpy, nd 20% received prior rdition therpy. Overll, 417 ptients received totl of 2,551 cycles of chemotherpy (Tble 2), with mjority of those cycles given s first-line tretment (57%). Fifty-six percent of ptients received second-line therpy, while 26%, 10%, nd 7% received third-, fourth-, nd fifth-line therpy, respectively. The men number of totl chemotherpy cycles per ptient ws 6.1 (3.5 cycles first line, 2.6 cycles second line, The Oncologist

3 Murillo, Koeller 1097 Tble 1. Ptient demogrphics (n = 417) Men/medin ge (yers) 67/72 Age >69 40% Mle/femle 54%/46% Stge IIIb/IV 27%/73% Men PS score 1.2 PS % PS % Men BSA 1.86 m 2 Prior lung surgery 10% Prior lung rdition therpy 20% Prior chemotherpy 10% Abbrevitions: BSA, body surfce re; PS, performnce sttus. 2.8 cycles third line, 2.7 cycles fourth line, nd 2.4 cycles fifth line). The 6.1 cycles of overll chemotherpy required totl of 6.1 months to dminister. Eighty-three percent of ptients received chemotherpy combintion s first-line tretment. Combintion chemotherpy ws lso used s second-line (42%) nd third-line (23%) tretment. A vriety of gents nd regimens ws identified (Tble 3). Gret vribility in tretment ws seen t ll clinics nd cross ll lines of therpy. No consistent ptterns of tretment were identified mong the clinics. For poorer PS ptients (PS score 2), crbopltin plus pclitxel ws still the primry regimen used, lthough 26% of ptients received single-gent first-line tretment, compred with 18% for the totl popultion. Also, only 38% nd 13%, respectively, received second- nd third-line therpy compred with 56% nd 26%, respectively, for the totl popultion. Tretments for ptients >70 yers of ge were similr to those of poorer performnce ptients, with crbopltin plus pclitxel being the primry regimen nd 26% of ptients receiving single gents s first-line therpy. Also, 46% nd 17% of ptients were ble to receive secondnd third-line therpy, respectively. The primry difference in tretment identified between stge IIIb nd IV ptients ws the use of concurrent rdition therpy (XRT). Fifty-eight percent of stge IIIb ptients received concurrent XRT with the first cycle of chemotherpy, compred with only 14% for stge IV ptients. However, the progression of tretment from firstto second- to third-line nd greter therpy ws similr between the two stges. One hundred eighty-one ptients (43%) received chemotherpy within 1 month ( 31 dys) of deth. Of those, 39% received first-line, 28% received second-line, nd 21% received third-line tretment. For ptients who received Tble 2. Chemotherpy tretment Ptients (%) 417 (100%) Cumultive 1,451 chemotherpy (57%) cycles (%) Men cycles per ptient Averge months in line of therpy Line of therpy (56%) 601 (24%) Overll number of cycles = 2, (26%) 311 (12%) 43 (10%) 115 (5%) 30 (7%) 73 (2%) chemotherpy within 2 weeks ( 14 dys) of deth (20%), 39% received first-line, 28% received second-line, nd 18% received third-line tretment (Tble 4). Looking specificlly t gefitinib (for which use ws minly protocol bsed nd with U.S. Food nd Drug Administrtion pprovl coming ner the end of the dt cpture period), 19% of ptients received tretment within 1 month of deth nd 10% of ptients received tretment within 14 dys of deth. Ptients on verge hd received 2.1 lines of therpy t the time of deth. The men nd medin times from lst chemotherpy tretment to deth were 2.6 nd 1.6 months, respectively. Discussion The vilbility of new ctive gents hs lengthened the chemotherpy tretment timeline of dvnced NSCLC, nd thus my lso hve incresed the likelihood of receiving tretment closer to the time of deth. From these dt, 43% of ptients received chemotherpy within 1 month of deth, compred with 11% [14], 26% [15], nd 33% [15] reported from other trils. Chemotherpy within 2 weeks of deth ws seen in 20% of ptients in this study, compred with 16% reported in previous study [16]. The overll rtes of tretment within 1 month nd 2 weeks of deth in this study re higher thn those published previously. This evlution is more comprehensive in tht it identified the chemotherpy regimen nd the lines of therpy given from the initition of tretment to deth. For ptients who received chemotherpy within 1 month of deth, 88% received first-line (39%), second-line (28%), or third-line (21%) therpy. For ptients who received chemotherpy within 2 weeks of deth, 85% received first-line (39%), second-line (28%), or third-line (18%) therpy. At the time of deth, the mjority of ptients were receiving second-line therpy. Unfortuntely, we cptured only the strt-of-tretment PS score, nd did not cpture PS with subsequent lines of therpy becuse of the inconsistency of informtion vilble through this retrospective dt cpture. Also s

4 1098 End-of-Life Chemotherpy for NSCLC Tble 3. Chemotherpy regimens First line Second line b Third line c Crbopltin + pclitxel (37%) Docetxel (22%) Gefitinib (23%) Crbopltin + pclitxel + XRT (18%) Gemcitbine (14%) Docetxel (20%) Docetxel (7%) Gemcitbine + vinorelbine (13%) Gemcitbine (14%) Crbopltin + gemcitbine (6%) Vinorelbine (11%) Vinorelbine (14%) Crbopltin + docetxel (5%) Gefitinib (9%) Gemcitbine + vinorelbine (6%) Gemcitbine (5%) Crbopltin + pclitxel (4%) Pclitxel (3%) Vinorelbine (4%) Crbopltin + gemcitbine (4%) Gemcitbine + docetxel (3%) Gefitinib (2%) Crbopltin + docetxel (3%) Pclitxel + XRT (2%) Gemcitbine + vinorelbine (2%) Cispltin + gemcitbine (3%) Cispltin + vinorelbine (2%) Crbopltin + docetxel + XRT (2%) Gemcitbine + docetxel (2%) Crbopltin + pclitxel (2%) Overll number of cycles = 2, different regimens or gents were identified (84% combintions). b 29 different regimens or gents were identified (42% combintions). c 21 different regimens or gents were identified (23% combintions). Abbrevition: XRT, rdition therpy Tble 4. Time to deth from lst chemotherpy tretment 14 Dys 31 Dys n of ptients Percent 20% 43% Line of therpy: % 1: 39% 2: 28% 3: 18% 4: 10% 5: 4% 1: 39% 2: 28% 3: 21% 4: 6% 5: 5% Men/medin time from lst chemotherpy to deth: 2.6/1.6 months. Men line of therpy t time of deth: second line. result of consistency problems, we were unble to cpture cuse of deth. In ddition, we were unble to get hndle on physicin ptient interctions tied to the decisions mde relted to the progression of tretment. These dt demonstrte n incresed use of chemotherpy ner or t the time of deth. As described by Erle et l. [18], ggressive tretment my be prt of the reson. However, some of this behvior my ctully be relted to the vilbility of more tretment choices for dvnced NSCLC. The potentil of using trgeted therpies s longer-term mintennce tretment hs been reviewed nd this could be one justifiction for ptients receiving therpy nerer to the time of deth [19]. However, in our dtbse, the percentge of ptients receiving gefitinib ner the end of life ws not higher thn those receiving other chemotherpy. Another potentil fctor my be the physicin s inbility to predict the life expectncy of dvnced NSCLC ptients. Also, with the vilbility of medicl informtion on the Internet nd direct-to-consumer dvertising, ptients come to physicins sking for nd sometimes, lmost demnding specific or dditionl tretment. This report is missing informtion relted to the decision process ssocited with the progression of therpy from first- to second- to third-line nd greter tretment. Also, it is missing the PS score t lst line of therpy nd cuse of deth. Prospective evlutions including ptient fctors, PS, detiled disese-relted informtion, nd the chemotherpy tretment given ner or t the time of deth in the dvnced NSCLC ptient popultion cn help define its ppropriteness. However, we hope this report fosters dditionl dilogue nd follow-up studies relted to the ppropriteness of therpy t or ner the end of life for dvnced NSCLC ptients. Acknowledgment This study ws funded by reserch grnt provided by Eli Lilly & Compny. Disclosure of Potentil Conflicts of Interest J.K. hs cted s consultnt for BMS snofi-ventis. The Oncologist

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