Osteosarcoma: A Meta-Analysis and Review of the Literature

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1 A Review Pper Osteosrcom: A Met-Anlysis nd Review of the Literture Jill C. Friebele, MD, Jeffrey Peck, MD, Xueling Pn, PhD, Mhmoud Abdel-Rsoul, MS, MPH, nd Joel L. Myerson, MD Abstrct Over the pst 30 yers, tretment dvnces nd the ddition of neodjuvnt chemotherpy hve led to improved 5-yer survivl in ptients with osteosrcom. More recent literture suggests the overll prognosis remins highly vrible, with little improvement since the introduction of neodjuvnt chemotherpy. Tumor necrosis is n importnt predictor of ptient prognosis. Necrosis of more thn 90% correltes with overll survivl (OS) pproching 75%. We reviewed the history of osteosrcom tretment nd survivl nd performed met-nlysis of the literture. Forty rticles were included in the study. Five-yer OS ws 63% (95% confidence intervl, 60%-66%) in studies tht included ptients with metsttic nd nonmetsttic disese nd 71% (95% confidence intervl, 67%-76%) in studies tht included only ptients with nonmetsttic disese. Fifty percent of the ptients in the studies of those with nonmetsttic osteosrcom chieved 90% necrosis on histology. Five-yer OS nd number of ptients chieving 90% necrosis re consistent with previous reports. Reserch is needed to improve tretment regimens nd ptient outcomes. Osteosrcom, primry mlignnt tumor of the skeleton, is chrcterized by direct formtion of immture bone or osteoid tissue by tumor cells. The World Helth Orgniztion histologic clssifiction of bone tumors divides osteosrcom into centrl nd surfce tumors nd recognizes number of subtypes within ech group. 1 The present review refers only to the clssic centrl high-grde primry osteosrcom of bone, which represents bout 90% of ll osteosrcom cses. Clssic osteosrcom represents bout 15% of ll biopsy-nlyzed primry bone tumors. 1 It is the third most common type of neoplsi, preceded by leukemi nd lymphom mong older children nd dolescents ged 12 to 18 yers. 2 High-grde primry osteosrcom is the most common primry skeletl tumor of childhood nd dolescence, with n overll nnul incidence of 5.6 cses per million children under ge 15 yers. 3-5 Pek incidence is in the second decde of life, nd mles re ffected slightly more often thn femles. 2,6 The period of highest incidence coincides with the growth spurt of the long bones. Osteosrcom preferentilly ffects the metphysis of long bones, the 3 min sites being distl femur, tibi, nd proximl humerus. 2 Historicl Perspective For most of the 20th century, the 5-yer survivl rte for clssic primry osteosrcom ws under 20%. 7 In the 1970s, the first revolution in osteosrcom tretment rrived with the introduction of djuvnt chemotherpy, which incresed survivl rtes to 50% During this expnsion of reserch, severl chemotherpeutics (eg, vincristine, bleomycin, dctinomycin) were discrded for poor effectiveness, nd others (eg, cispltin, ifosfmide) were dded to doxorubicin nd methotrexte, improving 5-yer disese-free survivl to bout 70% in ptients with nonmetsttic osteosrcom. In nother significnt dvnce, djuvnt chemotherpy ws supplemented with intensive preopertive chemotherpy, resulting in 5-yer tumor-free survivl tht hs rnged from 50% to 75% for highgrde osteosrcom. 5,11,12 Adding neodjuvnt chemotherpy nd histologic response hs llowed for evlution of surgicl mrgins nd erly tretment of microscopic disese. Thus, effective limb-spring procedures cn be performed, nd the incidence of mputtion hs decresed from 90% to between 10% nd 20%. 13,14 However, sttisticl improvements in survivl ssocited with neodjuvnt tretment my simply dely time of recurrence nd metstsis. 15 In ddition, though chemotherpy hs improved survivl in osteogenic srcom, mny hve written tht this improvement ppers to reflect minly the increse in the intensity of the chemotherpy used, which lso leds to higher propensity for side effects. 16 Despite reserch nd dvnces in chemotherpy regimens, the prognosis of ptients with osteosrcom remins highly vrible nd often disml. Mirbello nd collegues 17 exmined osteosrcom incidence nd survivl rtes between 1973 nd 2004 nd found tht, with the introduction of neodjuvnt chemotherpy, survivl rtes improved significntly between 1973 nd 1983 nd between 1984 nd 1993, but there ws little improvement between 1993 nd Authors Disclosure Sttement: The uthors report no ctul or potentil conflict of interest in reltion to this rticle. December 2015 The Americn Journl of Orthopedics 547

2 Osteosrcom: A Met-Anlysis nd Review of the Literture The long-term outcome for ptients with metsttic disese is poor. Investigtors hve found tht 11% to 20% of ptients hve pulmonry metstsis t initil dignosis. About hlf of ptients without pulmonry metstses develop them lter in the disese course. 18 Survivl rtes for ptients with metstsis t initil presenttion hve rnged from 10% to 40%. 19 Recurrent disese still occurs in 30% to 40% of ptients, nd more thn 70% of them die of the tumor. 15 The survivors of osteosrcom re then t incresed risk for chronic medicl conditions nd dverse helth sttus becuse of the osteosrcom-relted tretments. 20 Prognostic Fctors It is importnt to understnd nd exploit the influences of different prognostic fctors in treting ptients with osteosrcom. 7 These fctors re importnt in estblishing the best Szendroi et l (0.63, 0.83) 2.11 Bcci et l, 14 long-term outcome (0.68, 0.81) 2.45 Bcci et l (0.59, 0.81) 2.03 Bcci et l (0.64, 0.78) 2.41 Bielck et l (0.63, 0.68) 2.75 Huben et l (0.48, 0.58) 2.58 Scully et l (0.59, 0.77) 2.24 Kger et l (0.23, 0.35) 2.48 Wilkins et l (0.88, 1.00) 2.49 Smelnd et l (0.66, 0.82) 2.31 Ozki et l (0.17, 0.38) 2.05 Bcci et l (0.59, 0.65) 2.71 Longhi et l (0.39, 0.58) 2.16 Mnkin et l (0.64, 0.72) 2.69 Kste et l (0.63, 0.88) 1.82 Donti et l (0.73, 0.98) 1.89 Bcci et l (0.63, 0.69) 2.73 Mtsuo et l (0.18, 0.42) 1.89 Kuhelj nd Jereb (0.37, 0.59) 1.97 Milou et l (0.11, 0.28) 2.24 Decke et l (0.73, 0.97) 1.93 Bcci et l, 39 predolescent group (0.62, 0.72) 2.57 Bcci et l, 39 older group (0.62, 0.68) 2.74 Bcci et l (0.64, 0.71) 2.70 Cho et l, 45 predolescents (0.48, 0.79) 1.59 Cho et l, 45 dolescents (0.44, 0.73) 1.66 Petrilli et l, 46 study III (0.45, 0.64) 2.16 Petrilli et l, 46 study IV (0.39, 0.57) 2.22 Lee et l, 48 mximl growth (0.74, 0.84) 2.58 Kim et l, 47 growth ptterns (0.69, 0.79) 2.62 Mirbello et l, 17 younger group (0.59, 0.64) 2.75 Mirbello et l, 17 older group (0.56, 0.62) 2.71 Wu et l (0.56, 0.69) 2.44 Ayn et l (0.55, 0.74) 2.15 Brulnd et l (0.67, 0.76) 2.60 Bielck et l (0.66, 0.70) 2.77 Bispo nd Cmrgo (0.35, 0.75) 1.22 Hsieh et l, 11 combined (0.44, 0.67) 1.95 Gonzlez-Billlbeiti et l (0.48, 0.72) 1.93 Kong et l (0.68, 0.77) 2.64 Kim et l (0.10, 0.44) 1.45 Lee et l (0.72, 0.81) 2.60 Kger et l (0.32, 0.70) 1.30 Worch et l (0.65, 0.69) 2.75 Overll (I 2 = 93.4%, P <.001) 0.63 (0.60, 0.66) Weights re from rndom effects nlysis. 0 1 Figure 1. Five-yer overll survivl for studies tht included ptients with metsttic nd nonmetsttic osteosrcom is represented by blck dimond. Gry box represents weight of study. Blck br represents 95% confidence intervl. Ech study s weight (fr right of grph) is bsed on number of ptients included in study. Abbrevition: CI, confidence intervl. 548 The Americn Journl of Orthopedics December

3 J. C. Friebele et l tretment for the individul. Thus, more ggressive tretments cn be strted in ptients with prognostic fctors tht pose higher risk of relpse. 21 A number of clinicl nd pthologic fetures (eg, tumor site, size, subtype; ptient sex nd ge; high lkline phosphtse or high lctte dehydrogense [LDH] vlues; multidrug resistnce; genetic vritions) hve prognostic significnce but often with contrdictory results becuse of lck of uniformity in ptient nlyses nd methods. 15 Survivl for ptients with primry osteosrcom hs been nlyzed with respect to tumor size nd loction. 7 Studies hve found higher survivl rtes for ptients with smller tumors (<10 cm) nd more distl tumor loctions. 7 These superior survivl rtes my be the result of erlier detection of tumors nd more options for surgicl resection of smller, distl tumors. Serum LDH levels hve helped in risk strtifiction of ptients. High LDH often occurred t time of relpse, nd relpse with high LDH correlted with poor prognosis. Meyers nd collegues 22 found tht 5-yer disese-free survivl ws 72% for ptients with norml LDH t presenttion nd 54% for ptients with elevted LDH t presenttion. Severl studies hve shown tht percentge of tumor necrosis on histology is strongly correlted with good prognosis. 21 Most groups now define good histologic response s less thn 10% vible tumor cells t time of surgery, nd poor response s more thn 10%. 23 Results of the Peditric Oncology Group (POG) protocol for loclized osteosrcom (POG 9351), or Children s Cncer Group (CCG) 7921, found 45% of ptients hd fvorble responses (>90% necrosis) fter preopertive chemotherpy. 24 However, severl clinicins hve recently questioned this finding. Overll, the prognosis for clssic osteosrcom of the extremity remins highly vrible, nd there hs been little improvement over the pst 20 yers. The prognosis for younger ptients, ptients with spinl disese, nd ptients with metsttic disese remins poor. Although some prognostic fctors hve been identified nd shown to predict good outcome, it seems few ptients hve these positive fctors. In this rticle, we describe the literture review nd met-nlysis we performed to better define recent survivl trends for ptients with primry osteosrcom. Methods The MEDLINE, PubMed, nd Cochrne dtbses were serched for eligible studies published in English between 2000 nd 2011 decde of recently reported reserch. We pplied the serch strtegy [ osteosrcom OR osteogenic srcom ] AND [ prognosis OR tretment OR survivl ] nd selected reports tht specificlly ddressed fctors predicting survivl in ptients with osteosrcom reports tht were limited to primry osteosrcom of the pelvis or extremity nd provided 5-yer overll survivl (OS) dt. Abstrcts of the selected rticles were independently reviewed, nd the inclusion nd exclusion criteri were pplied. We excluded bsic science studies nd those without peditric ptients, those without primry osteosrcom, those with periostel or prostel osteosrcom, nd those tht did not report 5-yer OS dt. Sttisticl Anlysis Number or proportion of ptients (whichever ws reported) with 5-yer OS nd number or proportion of ptients with 90% necrosis were extrcted from ech study. For ech tril, proportion of ptients with 5-yer OS nd 95% confidence intervls (CIs) nd proportion of ptients chieving 90% necrosis nd 95% CIs were determined. We lso clculted proportion of ptients with 5-yer OS nd proportion of ptients with 90% Bcci et l, 14 long-term outcome (0.68, 0.81) 6.54 Bcci et l (0.59, 0.81) 5.22 Huben et l (0.48, 0.58) 6.98 Scully et l (0.59, 0.77) 5.87 Wilkins et l (0.88, 1.00) 6.68 Smelnd et l (0.66, 0.82) 6.09 Kste et l (0.63, 0.88) 4.60 Bcci et l (0.63, 0.69) 7.49 Bcci et l (0.64, 0.71) 7.39 Lee et l, 48 mximl growth (0.74, 0.84) 6.96 Kim et l, 47 growth ptterns (0.69, 0.79) 7.10 Brulnd et l (0.67, 0.76) 7.03 Bispo nd Cmrgo (0.35, 0.75) 2.94 Gonzlez-Billlbeiti et l (0.48, 0.72) 4.92 Kong et l (0.68, 0.77) 7.16 Lee et l (0.72, 0.81) 7.03 Overll (I 2 = 89.4%, P <.001) 0.71 (0.67, 0.76) Weights re from rndom effects nlysis. 0 1 Figure 2. Five-yer overll survivl for studies tht included only ptients with nonmetsttic osteosrcom. Abbrevition: CI, confidence intervl. December 2015 The Americn Journl of Orthopedics 549

4 Osteosrcom: A Met-Anlysis nd Review of the Literture Szendroi et l (0.35, 0.57) 2.96 Bcci et l, 14 long-term outcome (0.64, 0.78) 3.30 Bcci et l (0.07, 0.23) 3.20 Bielck et l (0.53, 0.58) 3.51 Huben et l (0.23, 0.33) 3.43 Scully et l (0.29, 0.47) 3.14 Kger et l (0.51, 0.64) 3.31 Wilkins et l (0.77, 0.97) 3.10 Smelnd et l (0.49, 0.67) 3.14 Ozki et l (0.18, 0.40) 3.00 Bcci et l (0.61, 0.67) 3.49 Mnkin et l (0.44, 0.52) 3.47 Kste et l (0.39, 0.69) 2.63 Bcci et l (0.59, 0.65) 3.50 Milou et l (0.31, 0.53) 2.99 Decke et l (0.37, 0.71) 2.45 Bcci et l, 39 predolescent group (0.61, 0.71) 3.40 Bcci et l, 39 older group (0.61, 0.67) 3.51 Bcci et l (0.60, 0.66) 3.48 Cho et l, 45 predolescents (0.17, 0.46) 2.65 Cho et l, 45 dolescents (0.15, 0.41) 2.79 Petrilli et l, 46 study III (0.37, 0.56) 3.11 Petrilli et l, 46 study IV (0.11, 0.25) 3.31 Kim et l, 47 growth ptterns (0.39, 0.50) 3.40 Wu et l (0.33, 0.47) 3.31 Ayn et l (0.55, 0.74) 3.10 Hsieh et l, 11 combined (0.38, 0.62) 2.93 Gonzlez-Billlbeiti et l (0.29, 0.53) 2.91 Kong et l (0.38, 0.47) 3.42 Kim et l (0.47, 0.84) 2.34 Lee et l (0.42, 0.54) 3.37 Kger et l (0.43, 0.79) 2.33 Overll (I 2 = 95.5%, P <.001) 0.50 (0.45, 0.54) Weights re from rndom effects nlysis. 0 1 Figure 3. Proportion of ptients chieving 90% necrosis for studies tht included ptients with metsttic nd nonmetsttic osteosrcom. Abbrevition: CI, confidence intervl. Bcci et l, 14 long-term outcome (0.64, 0.78) 7.81 Bcci et l (0.07, 0.23) 7.64 Huben et l (0.23, 0.33) 8.02 Scully et l (0.29, 0.47) 7.55 Wilkins et l (0.77, 0.97) 7.49 Smelnd et l (0.49, 0.67) 7.55 Kste et l (0.39, 0.69) 6.64 Bcci et l (0.59, 0.65) 8.13 Bcci et l (0.60, 0.66) 8.10 Kim et l, 47 growth ptterns (0.39, 0.50) 7.97 Gonzlez-Billlbeiti et l (0.29, 0.53) 7.16 Kong et l (0.38, 0.47) 8.00 Lee et l (0.42, 0.54) 7.93 Overll (I 2 = 96.9%, P <.001) 0.50 (0.41, 0.59) Weights re from rndom effects nlysis. 0 1 Figure 4. Proportion of ptients chieving 90% necrosis for studies tht included only ptients with nonmetsttic osteosrcom. Abbrevition: CI, confidence intervl. 550 The Americn Journl of Orthopedics December

5 J. C. Friebele et l necrosis with corresponding 95% CIs of studies tht included ptients with nonmetsttic disese. We ssessed sttisticl heterogeneity mong trils included in the met-nlysis using the Cochrn Q test. Inconsistency ws quntified with the I 2 sttistic, which estimtes percentge of totl cross-studies vrition cused by heterogeneity rther thn chnce. 25 We considered I 2 higher thn 50% s indicting substntil heterogeneity. When substntil heterogeneity ws not found, the pooled estimte clculted on the bsis of the fixed-effects model ws reported using the inverse vrince method. When substntil heterogeneity ws found, the pooled estimte clculted on the bsis of rndomeffects model ws reported using the DerSimonin nd Lird 26 method, which tkes both within- nd between-study vritions into ccount. Publiction bis ws ssessed through funnel plots nd with Begg nd Egger tests. 27,28 Two-tiled P <.05 ws considered sttisticlly significnt. All sttisticl nlyses were performed with Stt/SE Version 11.0 (SttCorp). Results Our literture serch yielded 597 rticles. We cross-referenced these rticles with the MEDLINE, PubMed, nd Cochrne serch results using the sme keywords nd discrded the duplictes. The bstrcts of these rticles were then reviewed in detil. The 40 rticles 4,6,11,12,14,15,17-19,21,29-58 tht met our study inclusion criteri reported on studies tht included ptients with metsttic nd nonmetsttic osteosrcom. Becuse of the significnt difference in OS of ptients with metsttic disese, we lso nlyzed rticles tht included only ptients with nonmetsttic disese. Sixteen rticles 6,14,15,29,32-35,39,47,48,51,53,54,55,57 were included in the nlysis of ptients with nonmetsttic disese. Figure 1 shows 5-yer OS for ech of the 40 studies. For studies tht compred survivl of different groups of ptients, the survivl of ech group is shown seprtely. For exmple, Bcci nd collegues 39 divided ptients into dolescent nd predolescent groups nd reported 5-yer OS for ech. In our nlysis, we treted ech group independently nd reported their 5-yer OS seprtely. For ech study, 5-yer OS, weight of study, nd CI re included. Five-yer OS rnged from 19% to 94%. Anlysis ws performed to determine 5-yer OS for ll studies bsed on weight given to ech study. The rndom-effects model used for this nlysis (heterogeneity test, Q = ; P <.001; I 2 = 93.4%) showed 5-yer OS of 63% (95% CI, 60%-66%) for studies tht included ptients with metsttic nd nonmetsttic osteosrcom. Figure 2 shows 5-yer OS (rnge, 53%-94%) for ech of the 16 studies tht included only ptients with nonmetsttic disese. The rndom-effects model used for this nlysis (heterogeneity test, Q = ; P <.001; I 2 = 89.4%) showed 5-yer OS of 71% (95% CI, 67%-76%) for studies tht included only ptients with nonmetsttic disese. We then exmined percentge of ptients chieving 90% necrosis on histology in ech study. Severl studies included in the OS nlysis did not report percentge necrosis, leving 29 studies for the necrosis nlysis. Of these 29 studies, ll 29 included ptients with metsttic nd nonmetsttic disese, 4,6,11,14,15,18,19,21,29,31-36,37,39,40,43-47,49,50,54-57,59 nd 13 included only ptients with nonmetsttic disese. 6,14,15,29,32-35,40,47,54,55,57 Agin, becuse of the known difference in prognosis between ptients with metsttic disese nd ptients with nonmetsttic disese, we performed seprte nlyses, one for the combined dtset of ll 29 studies (Figure 3) nd the other for the 13 nonmetsttic studies (Figure 4). Rndom-effects models showed 90% necrosis for 50% of ptients in both nlyses: studies tht included ptients with metsttic nd nonmetsttic disese (95% CI, 45%-54%; heterogeneity test, Q = ; P <.001; I 2 = 95.5%) nd nonmetsttic studies (95% CI, 41%-59%; heterogeneity test, Q = ; P <.001; I 2 = 96.9%). We lso performed met-regression nlysis tht included necrosis s continuous vrible for both the overll dtset nd the nonmetsttic dtset. Five-yer OS ws plotted ginst percentge of ptients chieving 90% tumor necrosis for ech study. The results re plotted in Figure 5 (combined dtset). No evidence of publiction bis ws detected for 5-yer OS or percentge necrosis for the nlyses of the combined dtsets by either Egger test or Begg test. For 5-yer OS, Ps were.21 (Egger) nd.19 (Begg); for percentge necrosis, Ps were.10 (Egger) nd.62 (Begg). In ddition, no evidence of publiction bis ws detected for the nlyses of the nonmetsttic studies by either test. For 5-yer OS, Ps were.55 (Egger) nd.41 (Begg); for percentge necrosis, Ps were.42 (Egger) nd.95 (Begg). Discussion Five-yer OS ws 63% (95% CI, 60%-66%) for studies tht included ptients with metsttic nd nonmetsttic osteosrcom nd 71% (95% CI, 67%-76%) for studies tht included only ptients with nonmetsttic osteosrcom. These percentges fll within the rnge found in the literture. Mnkin nd collegues 37 reviewed 648 cses of ptients with osteosrcom treted t Msschusetts Generl Hospitl in 2004; OS ws 5-Yer Overll Survivl 100% 80% 60% 40% 20% 20% 40% 60% 80% 100% Percentge of Ptients Achieving 90% Tumor Necrosis Figure 5. Assocition of 5-yer overll survivl with proportion of ptients chieving 90% tumor necrosis in ech study. December 2015 The Americn Journl of Orthopedics 551

6 Osteosrcom: A Met-Anlysis nd Review of the Literture 68%. In 2011, Smpo nd collegues 60 reported 10-yer OS of 63% for ptients with metsttic nd nonmetsttic disese nd 73% for ptients with locl disese t presenttion. Five-yer OS rtes in the literture re consistently bout 70%. Ferrri nd collegues 61 reported 5-yer OS of 73% nd 74% for 230 ptients treted with 2 different neodjuvnt chemotherpy regimens between 2001 nd The consistency in 5-yer OS suggests OS of peditric ptients with osteosrcom hs plteued, nd there hs been no significnt improvement in survivl of ptients with osteosrcom over the pst 30 yers. Histologic response to preopertive chemotherpy is strongly ssocited with survivl in peditric osteosrcom. Bielck nd collegues 31 reported 5-yer OS of 75% to 80% for ptients who responded well to preopertive chemotherpy (>90% tumor necrosis) nd 45% to 55% for ptients who responded poorly (<10% necrosis). In our met-nlysis of studies tht included ptients with nonmetsttic osteosrcom, 50% chieved necrosis of more thn 90%. Percentge of ptients chieving necrosis of more thn 90% hs been bout 45%, ccording to pst reports. In 2012, Ferrri nd collegues 61 reported tht 45% of 230 ptients treted with neodjuvnt chemotherpy chieved more thn 90% tumor necrosis. Therefore, 5-yer OS nd percentge of ptients chieving 90% necrosis re consistent with previous reports, though this lso suggests these numbers hve remined constnt over the pst severl decdes. Despite its expnsive scle, our study hs severl importnt limittions. Dt were extrcted from published studies, nd individul ptient dt were not vilble, so we were not ble to ssess the effects of risk fctors (eg, tumor size, loction) on 5-yer OS. We could not correlte the proportion of ptients with 90% necrosis to 5-yer OS, s studies did not report OS by necrosis strt. Also, becuse our numbers were derived from published studies, they my not ccurtely represent outcomes in the community s whole. In ddition, severl successive studies my contin duplicte ptient cses. We limited our serch to studies published since 2000 to include ptients recently dignosed nd treted for osteosrcom; however, severl studies published fter 2000 lso included ptients dignosed nd treted before Severl of these studies re from countries outside the United Sttes nd my hve significntly different incidence of osteosrcom s well s tretment methods nd survivl rtes. Although this met-nlysis suggests 5-yer OS remins bout 70% for ptients with primry nonmetsttic osteosrcom, we cnnot settle on this conclusion becuse of the mny differences between the studies we included. Therefore, more studies of ptients dignosed nd treted within the pst 10 yers re needed to confirm our beliefs bout ptient survivl. Dr. Friebele is Attending Physicin, Vlley Children s Hospitl, Mder, Cliforni. Dr. Friebele ws resident physicin t Ohio Stte University Medicl Center, Columbus, Ohio, t the time the rticle ws written. Dr. Peck is Resident Physicin in Orthopedics, McLren Regionl Medicl Center, Flint, Michign. Dr. Pn is Reserch Scientist, nd Mr. Abdel-Rsoul is Senior Consulting Reserch Sttisticin, Center for Biosttistics, Ohio Stte University, Columbus, Ohio. Dr. Myerson is Professor of Orthopedics, Progrm Director for Orthopedics Residency Progrm, College of Medicine, nd Director of Srcom Services, Arthur Jmes Cncer Hospitl, Ohio Stte University, Columbus, Ohio. Address correspondence to: Joel L. Myerson, MD, Musculoskeletl Oncology, Arthur Jmes Cncer Hospitl, Ohio Stte University, Prior Hll, Suite 725, 376 W. 10th Ave., Columbus, OH (tel, ; fx, ; emil, joel.myerson@osumc.edu). Am J Orthop. 2015;44(12): Copyright Frontline Medicl Communictions Inc All rights reserved. References 1. Widhe B, Widhe T. Initil symptoms nd clinicl fetures in osteosrcom nd Ewing srcom. 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