ONCOLOGY LETTERS Osteosrcom in ptients below 25 yers of ge: An observtionl study of incidence, metstsis, tretment nd outcomes ZHIGANG NIE nd HAO PENG Deprtment of Orthopedics, Renmin Hospitl of Wuhn University, Wuhn, Hubei 430060, P.R. Chin Received Jnury 18, 2018; Accepted August 6, 2018 DOI: 10.3892/ol.2018.9453 Abstrct. Only few systemtic nd comprehensive studies hve focused on osteosrcom in children nd dolescents. In the present study, 3,085 ptients with osteosrcom were identified in the Surveillnce, Epidemiology nd End Results Progrm dtbse. The ptients were <25 yers of ge nd dignosed between 1973 to 2012. A retrospective study ws performed to investigte the fctors ssocited with tumor incidence, metstsis, tretment nd survivl. The results indicted tht the incidence of osteosrcom ws higher in mle ptients compred with femle ptients. In ddition, the incidence rte of osteosrcom ws higher mong mle nd femle ptients between the ges of 10 nd 19. Osteosrcom locted in the chest nd pelvic bones ws ssocited with metsttic disese; however, metstsis in two histologicl types, prostel nd periostel, ws infrequent. Survivl nlysis reveled the following were ssocited with poor outcomes: Sex, ptients dignosed between 1973 nd 1982, distnt metstsis, tretment without surgery or with rdition, tumor with poorly differentited or undifferentited grde, tumor size 100 mm, nd tumor in the pelvic bones. Ptient's whose histologic type ws prostel osteosrcom nd whose tumor ws locted in one of the limbs, or who underwent locl or rdicl excision, exhibited good survivl outcome. Survivl outcomes were rnked ccording to the type of surgery, from best to worst, s follows: Locl excision, rdicl excision, mputtion nd no surgery. In summry, the incidence of osteosrcom is higher in mle ptients compred with femle ptients. Furthermore, individuls between the ges of 10 nd 19 hve higher risk of osteosrcom. Osteosrcom locted in the chest nd pelvic bones hs high risk of metstsis. Limb slvge surgery my be the optiml tretment pproch for non metsttic osteosrcom. Correspondence to: Professor Ho Peng, Deprtment of Orthopedics, Renmin Hospitl of Wuhn University, 99 Zhngzhidong Rod, Wuhn, Hubei 430060, P.R. Chin E mil: penghowhu123@163.com Key words: osteosrcom, incidence, tretment, outcomes Introduction Osteosrcom is frequently dignosed in children nd dolescents (1). Ptients <25 yers of ge exhibit higher incidence nd constituent rtio compred with ny other ge group (2). Studies suggested ptients <25 yers of ge with osteosrcom constitute s seprte specific subgroup of the popultion (3,4). Mirbello et l (2) reported tht the epidemiologic fetures of osteosrcom were unique mong the 0 24; 25 59 nd 60 yers ge groups, therefore emphsizing the need to study the forementioned ge groups seprtely. In the present study, osteosrcom ws exmined in the younger ge groups by conducting systemtic study of ptients <25 yers of ge. Single center nd ntionwide studies on osteosrcom hve been indicted to provide limited smple size (5,6). The Surveillnce, Epidemiology nd End Results (SEER) progrm, which currently consists of 17 geogrphiclly defined registries nd covers ~26% of the U.S. popultion, is ble to provide lrge smple size. For osteosrcom, the SEER progrm provides informtion regrding tumor site, histologic type, surgicl type nd incidence, which re useful prmeters for clinicl reserchers. Therefore, the SEER progrm my ssist clinicins with regrd to erly dignosis nd optiml tretment of the forementioned tumor type. Previous studies hve primrily focused on ll types of tumors, prticulrly bone tumors in <25 yers of ge (7 10) or osteosrcom cses of ll ges (3,4,11). However, further systemtic nd comprehensive studies focusing on osteosrcom in children nd dolescents re required. In the present study, the incidence bsed on yer of dignosis, ge, sex, rce, region, nd metstsis ws exmined from different sites nd histologic types. In ddition, the study ssessed the risk fctors for survivl outcomes from 15 fctors, performed pirwise comprison of these fctors nd elucidted optiml surgicl options to provide dditionl knowledge regrding the chrcteristics of osteosrcom in ptients <25 yers of ge. The im of the present cohort study ws to identify useful fctors for the prevention nd tretment of osteosrcom. Mterils nd methods Dt source. All dt were obtined from the SEER progrm (https://seer.cncer.gov/) nd the SEER*Stt ppliction 8.3.4 softwre (Surveillnce Reserch Progrm, Ntionl Cncer
2 NIE nd PENG: EPIDEMIOLIGAL STUDY OF OSTEOSARCOMA Institute, Bethesd, MD, USA) ws used for nlysis. Ptients between 0 nd 24 yers of ge, who were dignosed between 1973 nd 2012 were selected for the present study. Histologic Type Interntionl Clssifiction of Disese (ICD) O 3 ws input s 9180 9187 nd 9192 9195, nd Primry Site Lbeled ws input s C40.0 C41.9 in the softwre to represent osteosrcom. A totl of 3,085 cses were vilble. Incidence, frequency nd survivl outcomes were nlyzed ccording to the following 15 fctors. Study design. A totl of 15 fctors, including ptient ssocited fctors, tumor ssocited fctors nd tretment ssocited fctors, were included in the present study. Ptient ssocited fctors consisted of yer of dignosis, sex, ge t dignosis, rce, Contrct Helth Service Delivery Ares (CHSDA) region, nd rurl or urbn. Tumor ssocited fctors included stge, grde, tumor size, lterlity, Histologic Type ICD O 3 nd Primry Site Lbeled. Finlly, tretment ssocited fctors consisted of surgery, surgery type nd rdition. The yer of dignosis ws divided into the following 4 groups: 1973 1982; 1983 1992; 1993 2002; nd 2003 2012. Age t dignosis ws divided s follows: 0 4 yers; 5 9 yers; 10 14 yers; 15 19 yers; nd 20 24 yers. Individuls were lso ctegorized s Cucsin, Africn descent or other, which included Americn Indin/Alsk (AK) Ntive nd Asin/Pcific Islnder. CHSDA region ws ctegorized s Est, Northern Plins, Pcific Cost nd Southwest. Rurl or urbn: Urbn for ptients in metropolitn re nd rurl for ptients not in metropolitn re. Stge ws divided into loclized, regionl nd distnt. Grde ws divided into well differentited, modertely differentited, poorly differentited nd undifferentited. Tumor size ws divided into the following groups: <50 mm; 50 99 mm; 100 119 mm; nd 120 mm. Lterlity ws divided into right nd left, nd surgery type ws divided into no surgery, locl excision, rdicl excision nd mputtion. Vrious histologic types, which hd smll smples in the univrite nlysis, were excluded, while osteosrcom, not otherwise specified, chondroblstic, fibroblstic, telngiecttic nd prostel were included. For Primry Site Lbeled the following were combined: C40.0 nd C40.1, upper limbs; C40.2 nd C40.3, lower limbs; C41.0 nd C41.1, skull nd mndible; C41.2 nd C41.3, vertebrl nd chest bones; C41.4, pelvic bones. Vribles tht hd incomplete dt mong the 3,085 ptients included surgery type, tumor size nd grde. Cses for the present study were vilble through the SEER progrm, including 1,976 cses for surgery type recorded since 1998, nd 1,074 cses for tumor size recorded since 2004. Therefore, in the survivl curve, the x xis for surgery type nd tumor size did not correspond to 40 yers. For tumor grde dt, 1,834 cses were vilble in totl, distributed throughout 1973 2012; however, there were numerous missing dt. Sttisticl nlysis. The SEER*Stt ppliction 8.3.4 softwre ws used for sttisticl nlysis of the dt. Rte session ws used to clculte incidence, nd frequency session ws used to clculte frequency. Incidence is indicted s the number per 1,000,000. Cse listing session ws used to collect the dt of ech ptient nd for further survivl nlysis. The SPSS softwre 17.0 (SPSS, Inc., Chicgo, IL, USA) ws used to perform the survivl nlysis, log rnk testing, pirwise comprisons, five yer survivl rte nlysis, univrite nlysis nd multivrite Cox regression nlysis. Associtions mong histologicl type, tumor site nd stge were nlyzed using χ 2 tests. P<0.05 ws considered to indicte sttisticlly significnt difference. The forementioned 15 fctors were used to plot survivl curves, nd in log rnk testing, pirwise comprisons, five yer survivl rte nlysis nd univrite nlysis. A totl of 3 fctors, including grde, tumor size nd surgery type, hd incomplete dt, nd therefore, only 12 fctors were included in the multivrite Cox regression nlysis. Model 1 included ll 12 fctors, wheres Model 2 included 9 fctors subsequent to excluding 3 fctors, which exhibited no significnt difference in the univrite nlysis. The ssocition between surgery type nd survivl ws nlyzed s whole, but lso for ech stge nd grde. The numbers of ech cse, the sequence of survivl outcomes rnked from best to worst, nd pirwise comprisons were clculted. Results Osteosrcom incidence, ge t dignosis nd survivl for ll ge groups. As indicted in Fig. 1, the present study of osteosrcom ws performed in ll ge groups between 1973 nd 2012. In the line chrt two peks for osteosrcom incidence were indicted. The highest pek corresponded to the 0 24 ge group, nd the other pek corresponded to the 60 ge group (Fig. 1A). The mjority of osteosrcom cses were exhibited mong ptients between 10 nd 14 yers of ge (7.6 per million) nd between 15 nd 19 yers of ge (8.2 per million) (Fig. 1A). As indicted in Fig. 1B the rtios of osteosrcom were 56.8, 27.6 nd 15.6% for 0 24, 25 59 nd 60 yers of ge, respectively. A survivl curve indicted tht for the three ge groups, ptients between 0 nd 24 yers of ge hd the best prognosis, while ptients 60 yers of ge hd the worst prognosis (; Fig. 1C). Incidence of osteosrcom in ptients <25 yers of ge. The incidence of osteosrcom ccording to genertion, sex, rce, ge group nd CHSDA region re demonstrted in Tble I. The overll incidence rte of osteosrcom ws 4.5 per million. The time spn 1973 1982 hd the lowest incidence rte, while the following 3 decdes exhibited n increse in incidence rtes compred with previous decdes. However, differences mong the 3 decdes were not significnt (P>0.05). Mle ptients hd higher incidence of osteosrcom compred with femle ptients within ech decde. The incidence rte in mle ptients with osteosrcom incresed between 1973 nd 2003, nd decresed between 2003 nd 2012. Chnges in femle ptients, ccording to genertion, were not cler. Within ech decde, rces such s Americn Indin/Alsk Ntive nd Asin/Pcific Islnder, hd the highest incidence rte, followed by ptients of Africn descent nd Cucsin. As time progressed, the incidence rte of osteosrcom mong Cucsin ptients incresed. However, the incidence rte of osteosrcom decresed mong other rces, nd remined unchnged mong ptients of Africn descent. No visible trend over time ws observed for the 0 24 yer old group, but there
ONCOLOGY LETTERS 3 Tble I. Incidence of osteosrcom in ptients <25 yers of ge between 1973 nd 2012 over 10 yer intervls, ccording to sex, ge t dignosis, rce nd CHSDA region. Vribles 1973 1982 1983 1992 1993 2002 2003 2012 All Sex Mle 4.2 5.2 5.6 5.2 5.1 Femle 3.8 4.0 3.9 4.0 3.9 Age t dignosis (yers) 0 4 0.5 0.5 0.3 0.4 0.4 5 9 1.5 2.9 2.7 2.7 2.5 10 14 7.3 7.3 7.9 7.7 7.6 15 19 7.4 8.6 8.8 7.9 8.2 20 24 3.0 3.6 4.0 4.1 3.7 Rce Cucsin 3.7 4.4 4.6 4.5 4.3 Africn descent 4.8 5.0 5.1 5.3 5.1 Other 5.6 5.6 5.3 4.0 4.9 CHSDA region Est 3.8 4.1 4.1 4.1 4.0 Northern plins 3.7 4.5 5.1 5.4 4.6 Pcific cost 4.3 5.0 4.5 4.4 4.6 Southwest 4.1 4.9 5.6 4.6 4.8 All 4.0 4.6 4.8 4.6 4.5 CHSDA, Contrct Helth Service Delivery Ares. Figure 1. Osteosrcom incidence, ge distribution nd survivl, ccording to the ge of dignosis between 1973 nd 2012. (A) Rte of osteosrcom, ccording to the ge of dignosis. (B) Pie chrt nd (C) survivl nlysis curve of ptients with osteosrcom in the following ge groups: 0 24; 25 59 nd 60 yers of ge. (C) Survivl nlysis curve in the following ge groups: 0 24; 25 59 nd 60 yers of ge.
4 NIE nd PENG: EPIDEMIOLIGAL STUDY OF OSTEOSARCOMA Tble II. Incidence of osteosrcom in ptients <25 yers of ge between 1973 nd 2012, ccording to ge group nd sex. 1973 1982 1983 1992 1993 2002 2003 2012 All Age t dignosis (yers) Mle Femle Mle Femle Mle Femle Mle Femle Mle Femle 0 4 0.6 0.3 0.3 0.6 0.1 0.4 0.5 0.3 0.4 0.4 5 9 1.6 1.4 2.9 2.8 2.6 2.8 2.4 3.0 2.4 2.6 10 14 6.6 8.0 7.3 7.4 8.5 7.2 8.2 7.1 7.7 7.4 15 19 8.6 6.2 10.9 6.2 12.5 4.8 10.1 5.7 10.5 5.7 20 24 3.2 2.8 4.4 2.7 3.9 4.1 4.7 3.5 4.1 3.2 were significnt differences (P<0.05) within the ge group, with the highest incidence rte indicted in ptients between 10 nd 19 yers of ge, followed by those of 20 nd 24 yers of ge. No obvious findings for CHSDA regions were identified, except for the Est region, which hd the lowest incidence of osteosrcom. Incidence of osteosrcom ccording to sex nd ge. Tble II indictes the incidence rte of osteosrcom in mle nd femle ptients in different ge groups. It ws demonstrted tht femle ptients hd higher incidence rte of osteosrcom compred with mle ptients, between 0 14 yers of ge, prticulrly between the ges of 0 4, 5 9 nd 10 14 dignosed between 1983 nd 2002, 1993 nd 2012, nd 1973 nd 1992, respectively. When combining the 4 decdes, 1973 1982, 1983 1992, 1993 2002 nd 2003 2012, femle ptients hd higher incidence t 5 9 yers of ge (Tble II). Assocition mong histologic type, tumor site nd metstsis. Tble III indicted the ssocition between histologic type nd site with risk of metsttic disese. The distnt stge ws defined s metstsis. The results of the present study indicted tht the chest nd pelvic bones hd higher prevlence rte of metsttic disese, while the long bone of the upper limbs hd higher prevlence rte of metsttic disese compred with the lower limbs. Prostel nd periostel osteosrcom were two histologic types with low risk of metstsis. The five yer survivl rte, univrite nlysis nd pirwise comprisons. Tble IV summrized the five yer survivl rtes nd univrite nlyses for 15 fctors. Survivl curves nd the results of pirwise comprisons re presented in Fig. 2 for ptient ssocited fctors nd Fig. 3 for tumor ssocited fctors nd tretment ssocited fctors. Survivl outcome ws worst between 1973 1982, nd the following 3 decdes exhibited n improved survivl outcome. When ech of the 3 decdes ws compred with 1973 1982, ll results exhibited significnt differences (P<0.05), but comprisons within the 3 decdes indicted no differences (P>0.05). Femle ptients hd reltively good survivl outcomes compred with mle ptients (). The survivl outcome from best to worst mong the different ge groups ws s follows: 10 14; >5 9; >20 24; >15 19 nd >0 4 yers of ge, but there were no significnt differences in pirwise comprisons mong the groups (P>0.05). There were no significnt differences mong rces (P>0.05). In ddition, no significnt differences were observed mong CHSDA regions (P>0.05), except tht the region with the best outcome, Est, ws significntly different compred with the region with the worst outcome, Southwest (P<0.05). Ptients from rurl nd urbn res hd no significnt difference in survivl outcome (P>0.05). There were significnt differences in stge ccording to pirwise comprisons nd the entire comprison (). Well nd modertely differentited subtypes of grde corresponded to reltively good survivl outcomes compred with the poorly differentited nd undifferentited subtypes (P<0.05), but no significnt differences were demonstrted within well nd modertely differentited or within poorly differentited nd undifferentited subtypes (P>0.05). The survivl curve indicted tht lrge tumor size ws ssocited with reltively poor survivl outcomes, nd there ws significnt difference in survivl outcome between ptients with tumor size <50 mm nd ptients with tumor size >100 mm (P<0.05). There ws no significnt difference between tumors locted on the left nd right lterl (P>0.05). Prostel osteosrcom hd the best survivl outcome with five yer survivl rte of 89.0% nd ws significntly different from ll other histologicl types of osteosrcom (). The tumor sites rnked from best to worst survivl outcome were s follows: Skull nd mndible; lower limb; upper limb; vertebrl nd chest bones, nd pelvic bones. In pirwise comprisons, there were significnt differences between chest bones nd pelvic bones (P=0.001) nd between lower limbs nd upper limbs (). Ptients who underwent surgery hd reltively good survivl outcomes compred with those who did not (). The surgery types, which were rnked from best to worst for survivl outcome were locl excision, rdicl excision, mputtion nd no surgery. There ws no significnt difference between locl excision nd rdicl excision, ccording to pirwise comprisons (P>0.05), however, ll other types of surgery were ssocited with significnt differences (). Ptients who underwent rdition hd reltively poor survivl outcomes compred with ptients who did not receive rdition (). Assocition between surgery type nd survivl outcome. As the ssocition between surgery type nd survivl outcome my be confounded by other fctors, including stge nd grde of osteosrcom, survivl curves were plotted nd log rnk tests were performed for the sme stge or grde (Tble V). The frequency of mputtion s tretment for osteosrcom ws higher mong ptients with loclized stge of osteosrcom, while ptients with distnt stge of osteosrcom
ONCOLOGY LETTERS 5 Tble III. Assocition mong histologic type, tumor site nd stge in ptients <25 yers of ge with osteosrcom between 1973 nd 2012. Vribles Loclized, n (%) Regionl, n (%) Distnt, n (%) P vlue Histologic type ICD O 3 Osteosrcom, NOS 724 (35.0) 905 (43.8) 438 (21.2) Chondroblstic osteosrcom 117 (29.7) 208 (52.8) 69 (17.5) Fibroblstic osteosrcom 42 (35.9) 56 (47.9) 19 (16.2) Telngiecttic osteosrcom 39 (36.4) 52 (48.6) 16 (15.0) Osteosrcom in Pget disese of bone 1 (100.0) 0 (0.0) 0 (0.0) Smll cell osteosrcom 9 (39.1) 10 (43.5) 4 (17.4) Centrl osteosrcom 16 (32.0) 28 (56.0) 6 (12.0) Introsseous well differentited osteosrcom 1 (50.0) 1 (50.0) 0 (0.0) Prostel osteosrcom 69 (65.7) 31 (29.5) 5 (4.8) Periostel osteosrcom 16 (57.1) 10 (35.7) 2 (7.1) High grde surfce osteosrcom 1 (12.5) 4 (50.0) 3 (37.5) Primry site lbeled C40.0 Long bones: Upper limb, scpul, nd ssocited joints 118 (34.3) 149 (43.3) 77 (22.4) C40.1 Short bones of upper limb nd ssocited joints 5 (50.0) 5 (50.0) 0 (0.0) C40.2 Long bones of lower limb nd ssocited joints 796 (36.8) 973 (45.0) 394 (18.2) C40.3 Short bones of lower limb nd ssocited joints 13 (36.1) 17 (47.2) 6 (16.7) C41.0 Bones of skull nd fce nd ssocited joints 32 (36.8) 39 (44.8) 16 (18.4) C41.1 Mndible 23 (39.7) 30 (51.7) 5 (8.6) C41.2 Vertebrl column 13 (41.9) 13 (41.9) 5 (16.1) C41.3 Rib, Sternum, Clvicle nd ssocited joints 12 (27.3) 18 (40.9) 14 (31.8) C41.4 Pelvic bones, scrum, coccyx nd ssocited joints 22 (17.9) 59 (48.0) 42 (34.1) C41.9 Bone, NOS 1 (16.7) 2 (33.3) 3 (50.0) Sttisticlly significnt. P<0.05 ws considered to indicte sttisticlly significnt difference. P vlues were clculted by χ 2 tests. NOS, not otherwise specified; n, number; ICD, Interntionl Clssifiction of Disese. were not surgiclly treted. In ddition, mputtion ws indicted to be higher mong ptients with undifferentited grde of osteosrcom. In the comprison of surgery types mong ptients with the sme stge or grde of osteosrcom, results of survivl outcome bsed on surgery type were lmost identicl. The results of the present study indicted tht for types of surgery the best to worst survivl outcomes were s follows: Locl excision, rdicl excision, mputtion nd no surgery. The forementioned result ws lso indicted for the totl number of ptients. Therefore, locl excision my be the optiml choice for ptients with ny type of osteosrcom, conflicting with the previous notion tht mputtion is the optiml choice of tretment. In ddition, s indicted in the results of Tble V, rdicl excision my be n optiml choice for ptients with metsttic disese. Multivrite Cox regression nlysis. In the univrite nlysis, fctors with significnt differences included yer of dignosis, sex, ge t dignosis, CHSDA region, stge, grde, tumor size, histologic type, tumor site, surgery, surgery type nd rdition (P<0.05). The results of the multivrite Cox regression nlysis re indicted in Tble VI. Yer of dignosis, sex, ge t dignosis, CHSDA region, stge, histologic type, tumor site, surgery nd rdition were independent risk fctors in Model 1 of the multivrite Cox regression nlysis (P<0.05). In Model 2 of the multivrite Cox regression nlysis, independent risk fctors included yer of dignosis, sex, CHSDA region, stge, histologic type, tumor site, surgery nd rdition (P<0.05). Discussion At the strt of the present study, the distribution chrcteristics for the incidence of osteosrcom ws indicted ccording to ge. The results demonstrted tht ptients <25 yers of ge with osteosrcom hd reltively good survivl outcomes, but lso hd the highest rtio (56.8%) nd incidence (8.2 per million) mong ll ge groups. The forementioned result my be due to certin chrcteristics of this ge group, which remin unknown. Therefore, this specific ge group requires further study in terms of incidence, metstsis, survivl prognosis nd tretment options for osteosrcom, ccording to the forementioned 15 fctors. The lowest incidence rte of osteosrcom nd worst survivl outcomes were observed between 1973 nd 1982, while the subsequent 3 decdes hd the highest incidence rte nd best outcomes. Within these 3 decdes, incidences nd survivl outcomes minimlly chnged. The five yer survivl
6 NIE nd PENG: EPIDEMIOLIGAL STUDY OF OSTEOSARCOMA Tble IV. Five yer survivl rte nd univrite nlysis in ptients with osteosrcom <25 yers of ge between 1973 nd 2012. Univrite nlysis Vribles n (%) Survivl (95% CI) HR (95% CI) P vlue Yer of dignosis 1973 1982 357 (11.6) 50.1 (45.0 55.2) Reference 1983 1992 404 (13.1) 62.7 (58.0 67.4) 0.701 (0.576 0.852) 1993 2002 851 (27.6) 63.5 (60.2 66.8) 0.661 (0.557 0.784) 2003 2012 1,473 (47.7) 66.3 (63.6 69.0) 0.582 (0.493 0.687) Sex Mle 1,757 (57.0) 60.1 (57.7 62.5) Reference Femle 1,328 (43.0) 67.3 (64.8 69.8) 0.757 (0.675 0.849) Age t dignosis (yers) 0.014 0 4 49 (1.6) 54.1 (39.2 69.0) Reference 5 9 368 (11.9) 64.2 (59.1 69.3) 0.728 (0.468 1.131) 0.158 10 14 1,064 (34.5) 66.4 (63.5 69.3) 0.666 (0.437 1.014) 0.058 15 19 1,102 (35.7) 60.0 (57.1 62.9) 0.828 (0.545 1.258) 0.376 20 24 502 (16.3) 63.8 (59.5 68.1) 0.776 (0.504 1.194) 0.249 Rce 0.939 Cucsin 2,289 (74.2) 63.2 (61.0 65.4) Reference Africn descent 476 (15.4) 62.1 (57.6 66.6) 1.023 (0.877 1.194) 0.771 Other 296 (9.6) 62.6 (56.9 68.3) 0.985 (0.814 1.191) 0.872 CHSDA region 0.011 Est 843 (27.3) 65.8 (62.5 69.1) Reference Northern Plins 479 (15.5) 61.8 (57.3 66.3) 1.169 (0.981 1.394) 0.081 Pcific Cost 1,465 (47.5) 63.4 (60.9 65.9) 1.114 (0.970 1.280) 0.127 Southwest 295 (9.6) 56.5 (50.6 62.4) 1.394 (1.142 1.701) 0.001 Rurl or urbn 0.098 Rurl 264 (8.6) 60.8 (54.7 66.9) Reference Urbn 2,758 (89.4) 63.5 (61.5 65.5) 0.852 (0.704 1.031) 0.098 Stge Loclized 1,034 (33.5) 77.5 (74.8 80.2) Reference Regionl 1,305 (42.3) 64.7 (62.0 67.4) 1.640 (1.416 1.900) Distnt 562 (18.2) 31.1 (27.0 35.2) 4.442 (3.798 5.196) Grde Well 86 (2.8) 81.1 (72.5 89.7) Reference Modertely 125 (4.1) 78.0 (70.4 85.6) 1.142 (0.653 1.997) 0.641 Poorly 524 (17.0) 61.4 (56.9 65.9) 2.073 (1.307 3.287) 0.002 Undifferentited 1,100 (35.7) 64.5 (61.6 67.4) 2.015 (1.286 3.163) 0.002 Tumor size (mm) <50 127 (4.1) 79.5 (71.7 87.3) Reference 50 99 458 (14.8) 73.2 (68.7 77.7) 1.250 (0.809 1.930) 0.315 100 119 149 (4.8) 64.3 (55.9 72.7) 1.751 (1.082 2.836) 0.023 120 340 (11.0) 56.4 (49.9 62.9) 2.119 (1.376 3.263) 0.001 Lterlity 0.371 Right 1,364 (44.2) 50.0 (47.5 52.5) Reference Left 1,367 (44.3) 63.3 (60.6 66.0) 1.056 (0.937 1.191) 0.371 Histologic Type ICD O 3 Osteosrcom, NOS 2,223 (72.1) 60.8 (58.6 63.0) Reference Chondroblstic 407 (13.2) 62.4 (57.5 67.3) 0.912 (0.770 1.080) 0.286 Fibroblstic 122 (4.0) 69.9 (61.7 78.1) 0.732 (0.539 0.994) 0.045 Telngiecttic 109 (3.5) 70.2 (61.0 79.4) 0.774 (0.557 1.075) 0.127 Prostel 111 (3.6) 89.0 (82.9 95.1) 0.287 (0.180 0.457)
ONCOLOGY LETTERS 7 Tble IV. Continued. Univrite nlysis Vribles n (%) Survivl (95% CI) HR (95% CI) P vlue Primry site lbeled Upper limb 378 (12.3) 56.8 (51.5 62.1) Reference Lower limb 2,321 (75.2) 66.4 (64.4 68.3) 0.737 (0.627 0.867) Skull nd mndible 155 (5.0) 67.6 (60.0 75.2) 0.694 (0.511 0.944) 0.02 Vertebrl nd chest bones 79 (2.6) 48.2 (37.0 59.4) 1.301 (0.943 1.795) 0.109 Pelvic bones 135 (4.4) 31.1 (22.9 39.3) 2.339 (1.827 2.993) Surgery Yes 2,613 (84.7) 66.3 (64.3 68.3) Reference No 399 (12.9) 44.6 (39.5 49.7) 2.113 (1.831 2.438) Surgery type No surgery 244 (7.9) 42.4 (35.9 48.9) Reference Locl excision 208 (6.7) 75.3 (69.2 81.4) 0.310 (0.226 0.426) Rdicl excision 1,076 (34.9) 71.1 (68.2 74.0) 0.344 (0.281 0.422) Amputtion 389 (12.6) 61.7 (56.6 66.8) 0.494 (0.391 0.624) Rdition Yes 163 (5.3) 35.3 (27.7 42.9) Reference No 2,881 (93.4) 64.8 (63.0 66.6) 0.373 (0.308 0.450) Sttisticlly significnt. P<0.05 ws considered to indicte sttisticlly significnt difference. P vlues clculted by univrite nlysis. HR, hzrd rtio; CI, confidence intervl; n, number; ICD, Interntionl Clssifiction of Disese; NOS, not otherwise specified; CHSDA, Contrct Helth Service Delivery Ares. rte ws 50.1% prior to 1982 nd >60% subsequent to this yer. The incresed incidence of osteosrcom, following 1982, my be due to the dignostic improvements for osteosrcom. Numerous studies hve lso observed tht there ws improvement in survivl for ptients dignosed with osteosrcom subsequent to 1982, which ccording to the studies my be due to the introduction of chemotherpeutic regimens (12,13). Duffud et l (14) reported tht loclized high grde osteosrcom hd long term disese free survivl rte of <20% prior to the dministrtion of intensive chemotherpy nd 55 75% subsequent to the introduction of the forementioned tretment. The ptient derived orthotopic xenogrft model, developed over the pst 30 yers, is promising reserch method for effective individulized therpy, which hs been pplied to vrious types of cncer, including brest, ovrin, lung, cervicl, colon, stomch, pncretic, melnom, srcom, nd osteosrcom (15). Using the forementioned model, Murkmi et l (16) nd Igrshi et l (17) indicted tht the tumor trgeting Slmonell typhimurium A1 R is powerful tretment option nd they reported tht it ws ble to regress osteosrcom. The uthors of the forementioned studies lso used this model to screen drugs nd identify effective tretment drugs or drug combintions for osteosrcom (18,19). Sex ssocited differences reveled tht mle ptients hd higher incidence rte of osteosrcom compred with femle ptients, which ws consistent even within the sme rce nd region (dt not shown). The only exception ws tht femle ptients 5 9 yers of ge hd higher incidence rte of osteosrcom compred with mle ptients. The forementioned results my be due to the ctive bone growth reported in mles nd femles (20). It hs been reported tht mles undergo more rpid bone growth compred with femles (21). However, femles between the ges of 11 nd 13 hve been reported to be tller nd undergo rpid bone growth compred with ge mtched mles (22). Numerous studies hve reported tht s the height of n individul increses so does the risk of osteosrcom (20,23 25). A higher incidence rte of osteosrcom ws dditionlly observed in femle ptients between 0 nd 14 yers of ge in study by Mirbello et l (2) nd in femle ptients between 10 nd 14 yers of ge in study by Hom et l (26). Regrding sex ssocited differences in survivl, numerous studies (27,28) hve reported tht femles hve longer life spn compred with mles; results which confirm the present study's findings. Reserchers hve ttributed the forementioned survivl difference to the reltively poor response reported in mle ptients to chemotherpy, nd their high recurrence rte (29,30). In the present study it ws dditionlly proposed tht mles my exhibit symptoms in the long term nd therefore, do not prticipte ctively in tretment. Regrding ge, the highest incidence of osteosrcom ws mong those 10 19 yers of ge, followed by those between 20 nd 24 yers of ge, which my be due to the rpid bone growth of the forementioned ge groups. The optiml survivl rte ws observed in ptients between 10 nd 14 yers of ge nd between 5 nd 9 yers of ge, wheres the worst survivl rte ws observed in ptients between 1 nd 4 yers of ge. The survivl results of the present study were verified by
8 NIE nd PENG: EPIDEMIOLIGAL STUDY OF OSTEOSARCOMA Tble V. Assocition between surgery type nd survivl outcome in ptients <25 yers of ge with osteosrcom between 1973 nd 2012, ccording to stge nd grde. Stge (n=1,915) Grde (n=1,439) All Vribles Loclized Regionl Distnt Well Modertely Poorly Undifferentited (n=1977) Number No surgery 53 53 107 2 4 42 88 244 Locl excision 98 75 29 16 13 48 78 208 Rdicl excision 396 504 163 25 53 229 492 1076 Amputtion 101 235 101 8 12 91 238 449 Order of outcome Best 2 2 3 1 3 2 2 2 Reltively good 3 3 2 3 2 3 3 3 Reltively poor 4 4 4 2 1 4 4 4 Worst 1 1 1 4 4 1 1 1 Significnce No surgery vs. locl excision 0.031 0.011 0.622 0.523 0.005 No surgery vs. rdicl excision 0.046 0.724 0.113 No surgery vs. mputtion 0.478 0.001 0.385 0.994 0.033 Locl excision vs. rdicl excision 0.469 0.557 0.202 0.505 0.393 0.682 0.576 0.462 Locl excision vs. mputtion 0.092 0.243 0.589 0.037 0.358 0.165 0.087 0.001 Rdicl excision vs. mputtion 0.139 0.263 0.002 0.006 0.014 0.081 0.042 Sttisticlly significnt. P<0.05 ws considered to indicte sttisticlly significnt difference. P vlues were clculted by log rnk tests. n, number. Figure 2. Survivl nlyses, ccording to (A) yer of dignosis, (B) sex, (C) ge, (D) rce, (E) CHSDA region nd (F) rurl or urbn in ptients <25 yers of ge with osteosrcom between 1973 nd 2012. CHSDA, Contrct Helth Service Delivery Ares. other single center studies (31 33). Guillon et l (31) nlyzed 15 ptients <5 yers of ge with osteosrcom nd reported mortlity rte of 45% (7 ptients) within 5 yers of follow up, suggesting tht osteosrcom is highly invsive in ptients
ONCOLOGY LETTERS 9 Figure 3. Survivl nlyses, ccording to (A) stge, (B) grde, (C) tumor size, (D) lterlity, (E) histologic type, (F) tumor site, (G) surgery, (H) surgery type nd (I) rdition in ptients <25 yers of ge with osteosrcom between 1973 nd 2012. NOS, not otherwise specified. <5 yers of ge. Worch et l (32) reported tht the five yer survivl rte of children 5 yers of ge nd >5 yers of ge ws 51.9 nd 67.3%, respectively. Suglski et l (33) reported tht the five yer survivl rte of children <12 yers of ge nd >12 yers of ge ws 11 nd 57%, respectively. However, Hgleitner et l (34) reported n opposite trend, where the 5 yer overll survivl rte ws 70.6±0.8, 52.5±1.1, 33.3±0.9% in ptients 14, 15 19 nd 20 40 yers of ge, respectively. The reson for the decrese in survivl rte in young ptients remins uncler, however, the forementioned findings suggest tht tumors in ptients with different ges hve different biologicl chrcteristics. Furthermore, limb slvge surgery poses surgicl chllenges for skeletlly immture ptients, s it my cuse leg length inequlity in the long term (35). It hs been reported tht ptients <5 yers of ge undergo mputtion t higher rte, wheres only number of ptients receive chemotherpy (32). Miller et l (36) defined ptients t the stge of distnt in the SEER dtbse s metsttic, wheres ptients t the stge of loclized or regionl were defined s non metsttic. Miller et l (36), including other reserchers, hve reported tht ptients with metsttic osteosrcom hd reltively poor prognosis compred with ptients with loclized osteosrcom (37,38). The present study compred the forementioned three subtypes of osteosrcom nd the differences were reported s significnt for ll 15 fctors in pirwise comprisons nd the overll comprison. This my be due to the fct tht the predominnt fctor ssocited to survivl ws metstsis vs. non metstsis. Lee (39) reported tht the event free survivl (EFS) rte of Koren children nd dolescents with osteosrcom t 5 yers following dignosis ws 27.0 nd 65.3% with nd without metstsis, respectively. Kntr et l (40) reported tht the 5 yer EFS rtes were 67 nd 25% in ptients with non metsttic nd metsttic disese, respectively. The present study demonstrted tht the five yer survivl rtes in loclized, regionl nd distnt stges were 77.5, 64.7 nd 31.1%, respectively. Two fctors, grde nd tumor size, hd incomplete dt nd hve been rrely nlyzed in other studies. In the present study, tumors with grdes of well nd moderte differentition hd reltively good outcomes compred with those tht were poorly differentited nd undifferentited in the univrite nlysis, possibly due to the fct tht tumor differentition reflects tumor mlignncy. Lrger tumors were reported to hve reltively poor prognoses (41), which ws confirmed in the present study, where tumors >100 mm in size hd reltively
10 NIE nd PENG: EPIDEMIOLIGAL STUDY OF OSTEOSARCOMA Tble VI. Multivrite Cox regression nlysis in ptients <25 yers of ge with osteosrcom between 1973 nd 2012. Model 1 Model 2 Vribles HR (95% CI) P vlue HR (95%CI) P vlue Yer of dignosis 1973 1982 Reference Reference 1983 1992 0.649 (0.500 0.841) 0.001 0.657 (0.529 0.816) 1993 2002 0.611 (0.484 0.771) 0.594 (0.491 0.719) 2003 2012 0.528 (0.418 0.666) 0.507 (0.419 0.613) Sex 0.042 Mle Reference Reference Femle 0.866 (0.754 0.995) 0.042 0.805 (0.710 0.912) Age t dignosis (yers) 0.042 0.081 0 4 Reference Reference 5 9 0.859 (0.518 1.423) 0.554 0.837 (0.52 1.349) 0.466 10 14 0.726 (0.448 1.176) 0.193 0.716 (0.454 1.129) 0.151 15 19 0.909 (0.561 1.471) 0.697 0.832 (0.528 1.311) 0.428 20 24 0.920 (0.558 1.516) 0.743 0.902 (0.566 1.440) 0.667 Rce 0.452 Cucsin Reference Africn descent 1.123 (0.935 1.348) 0.214 Other 1.043 (0.818 1.332) 0.733 CHSDA region 0.003 0.035 Est Reference Reference Northern Plins 1.372 (1.101 1.711) 0.005 1.190 (0.978 1.448) 0.082 Pcific Cost 1.164 (0.978 1.385) 0.088 1.133 (0.971 1.323) 0.114 Southwest 1.515 (1.187 1.934) 0.001 1.378 (1.108 1.715) 0.004 Rurl or urbn 0.71 Rurl Reference Urbn 1.046 (0.824 1.328) 0.71 Stge Loclized Reference Reference Regionl 1.612 (1.360 1.911) 1.585 (1.360 1.848) Distnt 4.036 (3.357 4.853) 3.899 (3.292 4.616) Lterlity 0.944 Right Reference Left 0.995 (0.873 1.135) 0.944 Histologic type ICD O 3 Osteosrcom, NOS Reference Reference Chondroblstic 0.821 (0.669 1.008) 0.060 0.869 (0.721 1.046) 0.137 Fibroblstic 0.669 (0.464 0.965) 0.032 0.779 (0.567 1.070) 0.124 Telngiecttic 0.770 (0.538 1.102) 0.154 0.782 (0.553 1.107) 0.166 Prostel 0.365 (0.218 0.614) 0.354 (0.218 0.576) Primry site lbeled Upper limb Reference Reference Lower limb 0.737 (0.617 0.881) 0.001 0.777 (0.654 0.923) 0.004 Skull nd mndible 0.668 (0.316 1.495) 0.344 0.689 (0.494 0.960) 0.028 Vertebrl nd chest bones 0.834 (0.487 1.429) 0.509 0.982 (0.691 1.395) 0.917 Pelvic bones 1.625 (1.157 2.281) 0.005 1.612 (1.210 2.147) 0.001 Surgery Yes Reference Reference No 1.726 (1.434 2.077) 1.645 (1.391 1.946)
ONCOLOGY LETTERS 11 Tble VI. Continued. Model 1 Model 2 Vribles HR (95% CI) P vlue HR (95%CI) P vlue Rdition Yes Reference Reference No 0.600 (0.461 0.781) 0.548 (0.442 0.679) Sttisticlly significnt. P<0.05 ws considered to indicte sttisticlly significnt difference. P vlues were clculted by multivrite Cox regression nlysis. Model 1 excluded grde, tumor size nd surgery type, which hd incomplete dt in the univrite nlysis. Model 2 further excluded rce, rurl or urbn, nd lterlity, which hd no significnt difference in the univrite nlysis. HR, hzrd rtio; CI, confidence intervl; n, number; ICD, Interntionl Clssifiction of Disese; NOS, not otherwise specified; CHSDA, Contrct Helth Service Delivery Ares. poor outcomes compred with tumors <50 mm. Therefore, lrger tumor sizes my reflect more dvnced stge of tumor development. Miller et l (36) performed histologicl nlysis for ptients with osteosrcom of ll ges, mong which Pget diseses were reported to be more common in the elderly group ( 60 yers of ge). However, in the present study only one cse of Pget disese presented in the younger group (<25 yers of ge). In ddition, smll cell osteosrcom ws commonly ssocited with metsttic disese in the forementioned study, in contrst to the present study. Nkjim et l (41) reviewed 72 cses with smll cell osteosrcom, concluding tht this subtype of osteosrcom is highly ggressive nd less responsive to chemotherpy. The present study reveled two histologic types, prostel nd periostel osteosrcom, which were not ssocited with metsttic diseses. Prostel osteosrcom hd reltively good survivl outcomes compred with ny other type of tumor, in ccordnce with the study of Mnkin et l (42). Bcci et l (43) reported tht fibroblstic nd telngiecttic tumors hd significntly higher 5 yer overll survivl rtes, wheres chondroblstic nd osteoblstic tumors hd significntly lower 5 yer overll survivl rtes. The effect of histologic type on metstsis nd survivl my be determined by biologicl chrcteristics of the tumors, however, further investigtion is required. The results of the present study indicted tht the long bones of the four limbs were predilection sites for osteosrcom. Lee (39) further reported tht the most frequently ffected site in children nd dolescents ws the distl femur (52.3%). In the present study, extremity osteosrcom hd low metstsis nd reltively good outcome, while xil skeletl osteosrcom hd the highest metstsis nd worst outcome, confirming previous observtions by Jninis et l (44), who reported tht extremity tumors hd 2 nd 3 yer survivl rte of 50 nd 21%, respectively, nd xil skeletl tumors hd 2 nd 3 yer survivl rte of 19 nd 13%, respectively. Mezz et l (45) studied 20 ptients between the ges of 3 nd 19 with xil skeletl osteosrcom nd reported 5 yer overll survivl rte s low s 40%. Among 129 cses of osteosrcoms, Akyuz et l (46) observed 6 cses of xil skeletl osteosrcoms, in which mortlity occurred in 5 cses between three nd sixteen months subsequent to dignosis, indicting poor prognosis. In the present study, the recorded sites were divided into 5 types to provide detiled informtion of tumor site nd prognosis. According to the nlysis, the tumor types rnked from best to worst survivl outcome followed skull nd mndible, lower limb, upper limb, vertebrl nd chest bones, nd pelvic bones. An explntion for the forementioned results is tht xil skeletl osteosrcoms in vertebrl, chest nd pelvic bones my in close proximity to importnt orgns, vessels or nerves, therefore, mking complete resection difficult nd possibly contributing to poor survivl. The type of surgery ws nlyzed in detil in the present study. Previous met nlyses (47,48) hve reported tht limb slvge surgery confers better survivl compred with mputtion. Schrger et l (7) dditionlly reported the sme trend in children nd dolescents. Once modern prosthetics becme vilble in the 1970s, there ws n increse in limb slvge surgeries performed, which corresponded to survivl outcomes in comprison to mputtion (7). It hs been reported tht limb slvge surgery is the optiml choice in 85% of children ptients with osteosrcom (49,50). Limb slvge surgery my provide better outcomes compred with mputtion, s mputtion cn cuse psychologicl nd functionl impirment in young ptients (51,52). Furthermore, the present study compred survivl outcomes mong different types of surgery of the sme stge or grde to exclude confounding fctors nd provide relible results, s fvorble outcomes my be due to mild disese rther thn type of surgery. According to the order of best to worst survivl outcome reported in the present study, surgery provided better outcomes compred with non surgicl tretment pproches, while excision provided better outcomes compred with mputtion. Therefore, lthough removing the entire tumor my be the idel choice for the tretment of osteosrcom, excessive excision negtively ffects body recovery. An interesting finding in the present study ws tht ptients with metsttic diseses hd better survivl rte when rdicl excision ws chosen s tretment option for osteosrcom, possibly due to the fct tht metsttic tumors tend to be lrger nd require to be thoroughly removed. Therefore, rdicl excision should be recommended for ptients with metsttic diseses. Picci et l (53) identified indequte mrgins in surgery s risk fctor for poor prognosis, confirming to n extent the results of the present study.
12 NIE nd PENG: EPIDEMIOLIGAL STUDY OF OSTEOSARCOMA The results of the present study initilly indicted poor outcomes in ptients who underwent rdition, however, further nlysis indicted tht the forementioned result ws not entirely vlid. A totl of 11.2% ptients with metsttic diseses hd undergone rdiotherpy, wheres 3.9% of ptients with non metsttic diseses hd undergone rdiotherpy (dt not shown). Therefore, higher number of ptients with metsttic diseses hd received rdiotherpy, indicting tht the observed negtive effect of rdiotherpy ws becuse ptients with metsttic diseses hd reltively poor overll prognosis. The systemtic nlysis of the present study my provide useful informtion for guiding clinicl work. Mles ptients between 10 nd 19 yers of ge hd high incidence rte of osteosrcom, suggesting the requirement for n erly screening of this forementioned high risk popultion for osteosrcom. Chest nd pelvic bones were t high risk of metstsis, therefore, metsttic lesions should be checked mong high risk ptients. Yer of dignosis, sex, CHSDA region, stge, histologic type, tumor site, surgery nd rdition were demonstrted in the present study to be independent risk fctors in the multivrite Cox regression nlysis. In order to improve survivl rte, locl excision cn be used in the mjority of ptients with osteosrcom, nd rdicl excision is suggested for ptients with metsttic diseses. However, the present study presents certin limittions. Firstly, informtion regrding chemotherpy tretment is not vilble in the SEER dtbse, therefore extrcting informtion ssocited with the type of drugs used for chemotherpy tretments ws not possible. Secondly, no detiled record of the type of surgery ws vilble, therefore, determining for exmple if ptients hd undergone joint replcement ws not possible. Thirdly, the present study ws retrospective rther thn rndomized controlled tril, therefore, whether to perform limb slvge surgery or n mputtion depended on the doctors' suggestion nd the ptient's requirement rther thn rndom ssignment. Finlly, there were no therpy records of biologic mrkers nd no records of tumor recurrence. Despite the forementioned limittions, the present study incorported reltively lrge number of osteosrcom cses from the SEER dtbse, incresing the ccurcy of present study's results. Acknowledgements The uthors thnk the Ntionl Nturl Science Foundtion of Chin (Beijing, Chin). The uthors lso thnk the Ntionl Cncer Institute (Bethesd, USA), who provided ccess to the public SEER dtbse. Funding The present study ws supported by the Ntionl Nturl Science Foundtion of Chin (grnt, no., 81672154; Beijing, Chin). Avilbility of dt nd mterils The dtsets generted nd/or nlyzed during the current study re vilble in the Surveillnce, Epidemiology, nd End Results (SEER) repository, https://seer.cncer.gov/. Authors' contributions ZN cquired dt, nlyzed dt nd wrote the mnuscript. HP cquired dt, designed the study, revised the mnuscript nd gve finl pprovl of the version to be published. All uthors red nd pproved the finl version of the mnuscript. Ethics pprovl nd consent to prticipte Ethics pprovl nd consent to prticipte re not needed s this study is bsed on lredy existing dt from the Ntionl Cncer Institute. The present study ws pproved by the Ntionl Cncer Institute. Ptient's consent for publiction Not pplicble. Competing interests The uthors declre tht they hve no competing interests. References 1. Dmron TA, Wrd WG nd Stewrt A: Osteosrcom, chondrosrcom, nd ewing's srcom: Ntionl cncer dt bse report. Clin Orthop Relt Res 459: 40 47, 2007. 2. 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