H. Tsujii National Institute of Radiological

Sciences(NIRS)

Carbon-ion Radiotherapy for Retroperitoneal Sarcomas

XXII Congresso Nazionale AIRO Associazione Italiana di Radioterapia Oncologica Roma, Ergife Palace Hotel, 17-20 November, 2012

Contents 1.   Characteris,cs-of-C0ion-RT-2.   Unresectable-bone-&-so9-,ssue-sarcoma-3.   Bone-sarcoma-

1)  Sacral-chordoma-2)  Osteosarcoma-3)  Chondrosarcoma-

4.   So9-,ssue-sarcoma-5.   Retroperitoneal-sarcoma-including-

paracervical-tumor--1)  General-aspects-2)  Preliminary-results-3)  Update-results-

6.   Summary-

Neon Carbon Proton Neutron Pion Electron #0ray-γ0ray

��!$ ���

Mass -�� -: -�� -: -� -� -� -� -1/7 -� -1/1800 -: -0-

�% �&

π0-$0-

n-n-n-n-

n-n-

P- P-

P-P-

P-

P-

Carbon Carbon ion

C nucleus� 6+ �

CO2

CH4

n-n-n-

n-n-

P- P-

P-P-

P-

P-n-

P-P-

Hydrogen Proton P�1+�

Particles used for cancer therapy

1. Superior dose localization

Characteristics of Carbon Ion Beams

Cancer

Beam modifyingdevice Proton�X-

ray

He

Carbon

Carbon-ion-beam-produces--dense-ioniza,on-and-its-RBE-is-2~3-,mes-larger-than-X0rays.

Beam

2. High biological effets

Ion beams can be localizedprecisely in the target.

Dose Distribution

Depth (cm)

10

9

8

7

6

5

4

3

2

1

0

142 4 6 8 10 12

X - Ray

Proton

Bragg peak

Plateau Carbon Ion

b

aRela

tive

Dose

Tumor

Ionization density increases with depth, therefore the RBE increases as carbon ions travel deeper in the body and Peak/Plateu ratio (a/b) of RBE for carbon ion beam is largest.

Author Site No. Cont- Compli- Survivalrolled cation

Caterall (1979) Soft 28 75% 32% -Ornitz (1980) B&S 20 65% - -Salinas (1980) B&S 34 62% 12% 59%(5-62mo)Battermann(1981) B&S 22 36% 27% -Cohen (1984) B&S 51 47% 38% 39% (>2yr)Schmitt (1983) Soft 60 50% - -

(1982) Bone 24 50% 33% -Wambersie (1984) Soft 22 18% 18% -Duncan (1986) B&S 30 38% 50% -Schwarz (1998) Soft 1171 50% - -

Local Control, Complications and Survival in Neutron Therapy for Bone/Soft Tissue Sarcomas

0102030405060708090

100

0 10 20 30 40 50 60 70 80 90 100Carbon Dose (GyE)

Prob

abili

ty

Local Control

MajorComplication

Carbon*ion,Therapy,in,Bone,&,So4,Tissue,Sarcomas,,Local,Control,and,Morbidity,by,Dose,

50%-(3/6)-

67%-(10/15)-

81%-(13/16)-

87%-(19/23)-89%-

(26/29)-

0%-(0/6)-

0%-(0/15)-

0%-(0/16)-

6%-(4/61)-

33%-(9/27)-

70.4-GyE/16fx/4wk-

Pa>ent,Distribu>on,enrolled,in,Carbon,Ion,Therapy,,at,NIRS!(June,1994�July,2012)

Total 6,846

HAMT*� 3,769

Prostate 1586(23.2%) HAMT :1254

Bone & Soft tissue 854 (12.5%) HAMT :642

Head & Neck 812(11.9%) HAMT :489

Lung 696(10.2%) HAMT :117

Liver 437(6.4%) HAMT :212 Rectum

352(5.1%) HAMT :287

Gynecological 189(2.8%) HAMT �6

Eye 122(1.8%) HAMT :80

Pancreas 297(4.3%) HAMT :60

CNS 106(1.5%)

Skullbase 85(1.2%) HAMT :56

Esophagus 69(1.0%)

Lymph node 42(0.6%) HAMT :35

Lacrimal gland 21(0.3%)

Scanning 11(0.2%)

Miscellaneous 1167(17.0%) HAMT :531

HAMT*:Highly-Advanced-Medical-Technology

Contents 1.   Characteris,cs-of-C0ion-RT-2.   Unresectable-bone-&-so9-,ssue-sarcoma-3.   Bone-sarcoma-

1)  Sacral-chordoma-2)  Osteosarcoma-3)  Chondrosarcoma-

4.   So9-,ssue-sarcoma-5.   Retroperitoneal-sarcoma-including-

paracervical-tumor--1)  General-aspects-2)  Preliminary-results-3)  Update-results-

6.   Summary-

Clinical-Study-on--Unresectable-Bone-and-So9-Tissue-Sarcomas

Phase-I/II-Dose-Evalua,on-Study--June-1996-–-Feb-2000-n=59

Phase-II-Fixed-Dose-Study--April-2000-–-Feb--2011---n=520

Advanced-cases-including-pallia,ons-April-20050Feb-2011-n=284-

J,Clin,oncol(20),4466*4471.2002

J,Clin,oncol(26)562s.2008,

495-pts-(514-lesions)-Followed--for-6-months-or-more

-Evalua,on

•  Efficacy-depended-on-total-irradiated-dose.(52.8GyE/073.6GyE/16Fr)-

•  G3-acute-skin-reac,ons-were-observed-with-the-total-dose-of-73.6GyE/16Fr-(=-dose-constraint)

•  70.4GyE/16Fr-was-basic-effec,ve-dose.--

•  Beier-beam-delivery-to-avoid-severe-skin-reac,ons.--

•  no systemic metastases

0"

20"

40"

60"

80"

100"

120"

140"

160"

180"

1996" 1997" 1998" 1999" 2000" 2001" 2002" 2003" 2004" 2005" 2006" 2007" 2008" 2009" 2010"

pa,ents

Total--1068-pts--�1996.6�2011.2�-

Coun,ng-a-pa,ent-treated-twice-as-two-

Yearly-Number-of-Pts-with-B&S-Sarcoma-treated-with-Carbon-Ion-Radiotherapy-(C0ion-RT)

Fiscal-year

Age-: - -Median- - - -58(11087)-Sex-: - -Male - -- - -288-(58%)-

- -Female - - -207-(42%)-Tumor-Site-: -Pelvis - - - -388-(75%)-

- -Spine/Paraspine - ---96-(19%)-- -Extremi,es/-Others- --- ---30-(--6%)-

Histology-: -Bone - - - -405-(79%)--- -So9-Tissue - - -109-(21%)-

Bone,&,So4,Tissue,Sarcomas,April,2000,*,Feb,2011,:,,n=495,pts/,514,lesions,

The-current-protocol-is-mainly--for-unresectable-

sarcomas-using-70.4GyE/-16Fr-/4-weeks---

Bone,&,So4,Tissue,Sarcomas,April,2000,*,Feb,2011,:,,n=495,pts/,514,lesions,

" ""

No-of--pts

0"

20"

40"

60"

80"

100"

120"

140"

160"

180"177

Bone:-405(79%) So9-Tissue:-109(21%)

3.5 yrs after

Case 1. 81 y.o.M.

Case 3. 83 y.o. M.

Case 2. 57 y.o.F.

4.5 yrs after4 yrs after

Sacral-Chordoma

Total No.

No. per year

Method Local Control

Survival

5-Yr 10-Yr

USA: MGH 1) 21 1.1 Surgery 77 � - 50 �

Sweden: SUH 2) 39 1.1 Surgery 44 � 84 � 64 %

USA: MGH 3) 27 1.4 Surgery 72 � 82 � 62 %

USA: LBNL 4) 14 1.2 Surgery + He-ion 55 � 85 � 22 %

USA: Mayo Clinic 5) 52 2.5 Surgery 56 � 74 � 52 %

NIRS 183 12 (Max>25)

Carbon alone 77 � 85 % 74 �

Results of Treatment in Sacral Chordoma

1) J Bone Joint Surg. 1998 2) Cancer.2000 3)IJROBP.2006 4) IJROBP.1993 5) J Bone Joint Surg. 2005

Spinal-Chordoma-1996.602011.2-------n=183-pts-(-phase-I/II-and-II-study)

- -50year(%) --

Local-Control ---------77 ------- --

Overall-Survival ---------85 --------- - -

-

Follow0up-period-:--68-mths--(70155)-Median-Age-:--66--yo--(-26087)-Median-CTV-:-330-cm-

(Sacral-chordoma-:-Median-636-cm3-)-Ambulatory-was-remained-in-97%-Scia,c-nerve-dysfunc,on:-15pts-

Survival-,me-(months)

%

Re*calcifica>on,a4er,treatment

Osteosarcoma,of,the,Trunk

Osteosarcoma 70.4 GyE/ 16 fx/4 wks (4.4GyE x16)

Case 3. 14 yo. M. Case 2. 17 yo.M. Case 1. 80 yo.F.

2Yrs 4Yrs 5Yrs

�� ���� -�

2y��� 5y

Local--Control -�73 -61%-

Overall-Survival-----57%

-32%���-

Age -:Median-42-yo---(11083)-Tumor-site:-pelvis-61,--��spine/paraspine-15,--others-2-CTV-:-median---510cc---(6002290)-Follow0up-period:-mean--70-months-

Osteosarcoma-of-the-Trunk--1996.602009.6----n=78-pts

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

probability

0 12 24 36 48 60 72 84 96 108 132 156 180months

01

ê∂ë∂ï™êÕÉvÉçÉbÉg

Osteosarcoma,of,the,Trunk:,Result,By,Tumor,Volume,

Tumor-volume<500cc-(n=-38)-

�� �� ---2y�� 5y �500cc- --87 -------87%-≧ 500cc------ -57% �� 31%���-

Tumor-volume≧500cc(n=40)-

Logrank---p=0.0006-

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

probability

0 12 24 36 48 60 72 84 96 108 132 156 180months

01

ê∂ë∂ï™êÕÉvÉçÉbÉg

Tumor-volume<500cc-(n=-38)-

Tumor-volume≧500cc(n=40)-

Local-Control-Rate Overall-Survival-Rate

�� �� � -2y-5y

� 500cc- -65 -46%-≧ 500cc-50% -19%���-

Logrank---p=0.015-

A-smaller-tumor-volume-provided-a-beier-result.

Osteosarcoma,of,the,trunk,Institutes Treatment No of

Pts Site 5-yr Overall Survival (%)

All-case Resectable Unresectable

MGH 1,2 Surgery

Surgery +Proton/photon

26 S 31% - -

55 V 67% - -

Mayo Clinic3 Surgery 43 P 38% 38% -

Inst Orthop Rizzoli 4 Surgery 60 P 15% 30% 0%

COSS 5,6 Surgery 67 P 27% 34% 0% Surgery 22 S 30% 40% 0%

NCBT 7 Surgery 40 P 21% 26% - MSKCC 8 Surgery 40 P 34% 41% 10% (1/10) NIRS 9,10 Carbon ions 92 P+S 35% - 35%

45 (<500cc) 46% 46% S,-Spine;-P,-pelvis;-V,-various-1."Schoenfeld"AJ,"et"al."Spine!J!2010;"10:"708–14.""2."Ciernik"IF,"et"al."Cancer!2011;"117(19):"4522F30."

3."Fuchs"B,"et"al."Clin!OrthopRelat!Res!2009;"467:"510–8.""4."DonaK"D,"et"al."Eur!J!Surg!Oncol!2004;"30:"332–40."5."Ozaki"T,"et"al.!J!Clin!Oncol!2003;"21:"334–41.""6."Ozaki"T,"et"al.!Cancer!2002;"94:"1069–77."7."Ham"SJ,"et"al."Eur!J!Surg!Oncol!2000;"26:"53–60.""8."Kawai"A,"et"al."Clin!Orthop!1998;"348:"196–207."9."Imai"R,"et"al."Proceedings"of"NIRSFETOILE"2nd"Joint"Symposium"on"Carbon"Ion"Radiotherapy"2011;"NIRSFMF243:"38F45."10."Matsunobu"A,"et"al."Cancer!2012,"in"press.

•  Sex - - -:-M:F-=-40-:31-

•  Age- - -:-median:56-yo�(17-–-82)-

•  Tumor-Volume- -:-median:488-ml-(25�2900-cc-) •  Total-Dose(GyE)-:- -70.4GyE-was-applied-to-84%-pts-•  Histology -:"G2-or-worse-=-87%-pts

Chondrosarcoma-1996.6-–2009.8----n=71-pts--

Age-distribu,on---

10""""""""""20""""""""""""30""""""""""""40"""""""""""50"""""""""""""60"""""""""""70"""""""""""80""""""""""90"yo 0"

5"

10"

15"

20"

1" 2" 3" 4" 5" 6" 7" 8"

6-years-later--NED- Ambulatory-with-cane-.--Incon,nence--using-pads-workable

Chondrosarcoma"

----5-years-later--NED- ----5-years-later--NED- No-symptom-workable

No-symptom-workable

Prior-CIRT

A9er-CIRT

Th-8 3-rib

2007.9 2008.12

Chondrosarcoma-29yr-F-�Spacer-in-place,-64GyE/16Fx�

Before 24"a]er"CFion"RT 2007.9

2008.12

����������� �64GyE/16Fx�

�� ��15��

Contents 1.   Characteris,cs-of-C0ion-RT-2.   Unresectable-bone-&-so9-,ssue-sarcoma-3.   Bone-sarcoma-

1)  Sacral-chordoma-2)  Osteosarcoma-3)  Chondrosarcoma-

4.   So9-,ssue-sarcoma-5.   Retroperitoneal-sarcoma-including-

paracervical-tumor--1)  General-aspects-2)  Preliminary-results-3)  Update-results-

6.   Summary-

So4,Tissue,Sarcomas,treated,with,C*ions,at,NIRS�,

1996.6,�,2012.2, Total-No.:-139

Age� -14087-y/o��Median-55�-

Gender� -M:F=80�59-

Previous-Tx� Fresh-case -- -86-(62%)-

- ---Post0ope-rec-or-meta -53-(38%)-

Tumor-size� -1301871cm3-(Median-335cm3-)-

So4,Tissue,Sarcomas,treated,with,C*ions,at,NIRS,,(n=139)

Histo0pathology No. MFH 30 MPNST 14 Liposarcoma 14 Synovial-sarc 10 Others 71 Total 139

Sites No. Retroperitoneal&-Paracervical 56

Pelvis 54 Extremity 16 Others 13 Total 139

49y/o F�Rt Gluteal tumor ( "!ST)�

CTV : 708 cm3

Before C-ions 52 mo.

57y/o M�� myxoid chondrosarcoma of rt. buttock

Before ��� /((3

CR-(�-years-a9er-c0ion-RT)-�

�0,14����.,������.*��-)�+2)�'�-

0 24 48 72 96 120 1440

20

40

60

80

100

months

Perc

ent s

urviv

al

Results-of-C0ion-RT-in-So9-Tissue-Sarcomas�-1996.6-��2012.2�n=139-

Local-Control

Overall-Survival

- -20yr -50yr -100yr-Local-Control -77% -67% -67%-Overall-Survival -66% -40% -28%

Toxici>es,in,So4,Tissue,Sarcomas,in,a,total,of,139,pa>ents

•  ≧G3-Derma,,s-: - -1.5%-(2/139pts)-

•  ≧G2-Peripheral-Neuropathy-:-- - - - -11%--(10/91pts)-

•  ≧G2-Myelopathy-: - ---5% -(3/56pts) -

Original article

Carbon ion radiotherapy for localized primary sarcoma of the extremities:Results of a phase I/II trial

Shinji Sugahara a,b,⇑, Tadashi Kamada a, Reiko Imai a, Hiroshi Tsuji a, Noriaki Kameda c, Tohru Okada a,Hirohiko Tsujii a, Shinichirou Tatezaki d, For the Working Group for the Bone and Soft Tissue SarcomasaNational Institute of Radiological Sciences, Chiba; b Tokyo Medical University, Ibaraki; cChiba Cytopathology Diagnostic Center; dChiba Cancer Center, Japan

a r t i c l e i n f o

Article history:Received 23 May 2011Received in revised form 29 August 2012Accepted 12 September 2012Available online xxxx

Keywords:Sarcoma of the extremityLimb sparing therapyCarbon ion radiotherapyRadiation therapy

a b s t r a c t

Purpose: To determine the effectiveness of carbon ion radiotherapy (CIRT) for localized primary sarcomasof the extremities in a prospective study.Patients and materials: From April 2000 to May 2010, 17 (male/female: 12/5) patients with localized pri-mary sarcoma of the extremities received CIRT. The median age was 53 years (range: 14–87 years). Ninepatients had primary diseases and eight had recurrent diseases. Of the 17 patients, eight refused ampu-tation, and the remaining nine refused surgical resection. Tumors were located in the upper limbs in fourpatients and lower limbs in 13. Histological diagnosis was osteosarcoma in three patients, liposarcoma intwo, synovial sarcoma in two, rhabdomyosarcoma in two, pleomorphic sarcoma in two, and miscella-neous in six. The CIRT dose to the limb was 52.8 GyE for one patient, 64 GyE for three, 70.4 GyE for 13in 16 fixed fractions over 4 weeks. Records were reviewed and outcomes including radiologic response,local control (progression-free), and survival were analyzed.Results: The median follow-up was 37 months (range: 11–97 months). Radiological response rate was65% (PR in 11, SD in 5, and PD in 1). The local control rate at 5 years was 76%. The overall survival rateat 5 years was 56%. Of the 17 patients, 10 survived without disease progression. Four patients had localrecurrences, one was salvaged by repeated CIRT and the other three died due to systemic diseases. Dis-tant failure was observed in six patients. One patient suffered from femoral fracture (grade 3) andreceived surgical fixation 27 months after CIRT. No other severe reactions (grade 3) were observed.Conclusions: CIRT is suggested to be an effective and safe treatment for patients who refuse surgery forlocalized primary sarcomas of the extremities.

! 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2012) xxx–xxx

Management strategies for bone and soft tissue sarcomas(BSTSs) have changed dramatically in the last three decades [1].Amputation was considered first-line treatment for extremitysarcomas to prevent local recurrence. However, recent studiesindicate that amputation improves local control but confers noadvantage in terms of disease-free, disease-specific, or overall sur-vival (OS) [2]. Aggressive chemotherapy and/or radiation therapyin combination with limb preservation surgery is now the treat-ment of choice for most patients. For soft tissue sarcomas of theextremities, local control rates of more than 80% are achievedwith a combination of wide local excision and radiation therapy[3–5].

Wide excision surgery for sarcomas can entail large and complexdefects, particularly in patients with advanced and recurrentlesions. Although there are several nonsurgical treatments

available for patients who refuse surgery or are medically inopera-ble, their efficacy has yet to be established. In cases when BSTSs areunresectable, radioresistant, and/or located near critical organs,various particle beams offer promising results [6].

A phase I/II dose escalation study of carbon ion radiotherapy(CIRT) for BSTSs was conducted between 1997 and 1999 at theNational Institute of Radiological Sciences (NIRS), Chiba, Japan[7,8]. Among the high linear energy transfer (LET) particle beamsused on BSTSs, the carbon ion beam possesses unique physicaland biologic properties [9–13]. It has a well-defined range in thebeam-down direction and insignificant scatter to tissues in the lat-eral direction, while the energy release becomes large at the end ofits range (Bragg peak). More cell cycle-independent andoxygenation-independent, irreversible cell damage is thus inducedthan that observed with low LET radiation.

The purpose of this study was to evaluate the applicability ofCIRT for patients with localized primary sarcomas of the extremi-ties who refused surgery and preferred CIRT as local treatmentwith regard to local tumor control and normal tissue morbidity.

0167-8140/$ - see front matter ! 2012 Elsevier Ireland Ltd. All rights reserved.http://dx.doi.org/10.1016/j.radonc.2012.09.010

⇑ Corresponding author. Address: Department of Radiology, Ibaraki MedicalCenter, Tokyo Medical University, Ami-machi, Ibaraki 300-0395, Japan.

E-mail address: ssuga@tokyo-med.ac.jp (S. Sugahara).

Radiotherapy and Oncology xxx (2012) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Radiotherapy and Oncology

journal homepage: www.thegreenjournal .com

Please cite this article in press as: Sugahara S et al. Carbon ion radiotherapy for localized primary sarcoma of the extremities: Results of a phase I/II trial.Radiother Oncol (2012), http://dx.doi.org/10.1016/j.radonc.2012.09.010

So9-Tissue-Sarcomas--of-the-Extremi,es

Radiother"&"Oncol,"2012

So9-Tissue-Sarcomas-of-the-Extremi,es�-1996.6-�-2012.2-,-n=17

Age� -14087-y/o��Median-73�-Gender� -M:F=10:7-Previous-Tx� Fresh-case --9-

-----Post0ope-rec-or-meta -8-Tumor-size� -5901871cm3-(Median-301cm3-)-

Histo0pathology No. MFH 4 Liposarcoma 3 Synovial 2 Fibrosarcoma 2 Rhabdomyosarcoma 2 Others 4

Sites No. Lower-leg 6 Upper-leg 5 Foot 1 Hand 1 Forearm 2 Upper-arm 2

Sugahara,-et-al:-Radiother-Oncol,--on-line-,-2012.-

So9-Tissue-Sarcomas-of-the-Extremi,es�-1996.6-�2012.2�n=17-

Local-Control

Overall-Survival

Age-(Median):- -73-(14087)-Locally-no-recurrence:- -11-Surviving-in-9pats-Surviving-periods:-19~106mon.-(MST-56mo.

50yr-LC� -62� 50yr-Survival�41�-

Sugahara,-et-al:-Radiother-Oncol,--on-line-,-2012.-

Toxici>es,in,So4,Tissue,Sarcomas,of,the,Extremi>es

•  ≧G3-Derma,,s-: -0%-

•  Bone-fracture-: -0%-

•  No-recurrence-(Leg):-100%-(7/7)-•  ≧G2-Myelopathy-:-----6%-(1/17pts) -

Sugahara,-et-al:-Radiother-Oncol,--on-line-,-2012.-

49M��Liposarcoma of Rt Lower Leg

Before

8-years-

Sugahara,-et-al:-Radiother-Oncol,--on-line-,-2012.-

6 years after C-ion RT

Before

Figure"6.""Malignant"fibrous"hisKocytoma"of"the"le]"arm"received"70.4"GyE"in"16"fracKons"over"4"weeks"carbon"ion"radiotherapy."Complete"tumor""regression,"however"and"G3"neuropathy"were"observed"at"106"months"a]er"treatment.�"

Gd(+) MRI

Gd(+) MRI

MFH

Retroperitoneal--and-Paracervical-Sarcomas

Retroperitoneal,So4,Tissue,Sarcoma,(RP*STS) •  The-RP-space-is-the-site-of-origin-for-15%-to-20%-of--STSs.-•  Complete-surgical-resec,on-is-possible-in-less-than-70%-of-the-

primary-disease.-

•  Randomized-trials-have-demonstrated-that-the-addi,on-of-radia,on-to-surgery-unequivocally-improves-local-tumor-control-for-pa,ents-with-extremity-and-superficial-trunk-STSs.-

-→-This-finding-has-led-to-considerable-interest-in-the-use-of-surgery-plus-radia,on-for-pa,ents-with-RP0STSs.-

•  However,-the-efficacy-of-postopera,ve-external0beam-irradia,on-is-limited-by-the-inability-to-deliver-adequate-doses-of-irradia,on-on-account-of-the-dose-tolerance-limits-of-small-bowel,-spinal-cord,-stomach,-kidney,-and-liver.

→-Need-of-IORT-or-Ion-Beam-Therapy

*,Role,of,Radiotherapy,* •  In-RP0STS,-only-40–80%-of-the-pa,ents-are-resectable-and-microscopic-or-even-gross-residual-disease-is-o9en-present-postopera,vely.-

•  Surgery-alone-results-in-50year-local-control-rates-<50%.-•  The-local-control-rate-with-surgery-and-radia,on-(>60Gy)-is-more-than-double-that-seen-with-surgery-alone.-

•  Although-uncertainty-exists,-one-could-speculate-that-improved-local-control-could-affect-OS-by-improved-LC,-as-well-as-a-reduced-risk-of-DM.

Retroperitoneal,So4,Tissue,Sarcoma,(RP*STS)

Percent,10*year,actuarial,outcomes,according,to,primary,site

Ia bWbOY S R W HS S W Sa 5 0+

F VS 5 ) ,-* bOYaS

;W SO S% S WTW ,, /( 4( (()

;W OS O O W %T SS ./ .0 ( /

C OY Y ,( 0+ 4( (()

Ballo-MT,-et-al:-IJROBP-67:-1580163,-2007

Prognos>c,factors,independently,associated,with,outcomes,for,pa>ents,with,RP*STS,

Ia bWbOY S R W =O O - eSO bOYaS

;W SO S% S WTWa bWbOY

C c%U ORS 1* ( ((.S SRWO S%U ORS -)

?WUV%U ORS ,);W O S O O W %T SS a bWbOY

C c%U ORS 1* ( (,S SRWO S%U ORS /0

?WUV%U ORS -/

C OY Y ESUO WbS S S W O UW .* ( ()G W WbS S S W O UW ++G W O e RW SO S S S O W -0 ( ((*HS a S RW SO S S S O W */8US n.- e -, ( (-

� 8US 6.- e +( �

*-Mul,variate-analysis. Ballo-MT,-et-al:-IJROBP-67:-1580163,-2007

Kaplan-Meier local control curve according to external-beam radiation therapy dose.

•  The local control rate with surgery and adjuvant radiation is more than double that seen with surgery alone.

•  However, analyzing local control according to EBRT dose (≤50 Gy or >50 Gy) revealed no improvement with higher doses. Ballo-MT,-et-al:-IJROBP-67:-1580163,-2007

Prognos>c,factors,by,mul>variate,analysis,in,RP*STS

LO WOPYS ?H 1- :C OY Y 5 .+ � � �

DOYS US RS / 1, * *0%*/ 0 ( (()G W WbS a RS S W SR O UW , /0 ) ,1%)- + ( ((1

HJ R S W a a ( /0 ( .1%( 00 4( ((()FbS OYY a bWbOY 5 00

DOYS US RS * (. ) )-%+ .0 ( ()-?WUV W S SRWO S U ORS * 0, ) *-%. ,- ( ()+

Ia US e: YS S S S W ) (( %GO WOY S S W ) +1 ( .-%* 1, ( +1(K S S OPYS + -+ ) .1%/ +/ ( (((0Abbrevia,ons:-HR-=-hazard-ra,o;-CI-=-confidence-interval;-AI-=-Adriamycin/ifosfamide;-IdUrd-=-iododeoxyuridine;-GT-=-gemcitabine/Taxotere.

Feng M, et al. (2007) IJROBP 69;103 – 110.

Local-control-by-tumor-margin-status,-tumor-size,-and-median-radia,on-dose.

Feng M, et al. (2007) IJROBP 69;103 – 110.

Surgical-margin Tumor-size Radia,on-dose

Treatment-outcomes-of-IORT0treated-pa,ents--with-RP0STS

GO O S S 8YS WO S OY *(((

GS S S SOY *((*

>WS VS SOY *(()

IW RSYO S OY )11+

B S WS *((.

J SO SIa US e eS eS eS eS eSFHJ )->e )->e )->e *(>e )->e<9HJ ,-g-( ,>e ,->e ,->e ,(g-->e ,->e

E T O WS +* 0/ +/ +- ./

DSRWO T YY c%a ++ ,* +0 1. +(

G W SO S K SO SR )* ,+ *1 % +1HS a S *( ,, 0 % .)

DO W OYS S W 1, 00 % % 0*

-%e Y OY Y .* -1 -1 +/ ,( -%e ;D=I 0* -/ -, EH -(-%e Ia bWbOY ,- ,/ -( ,* .*-%e ;=I -- +) +0 +. *0

AbbreviaKons:"DFS"""diseaseFfree"survival;"DMFS"""distant"metastasis–free"survival;"NR"""not"reported.

CLINICAL INVESTIGATION Sarcoma

CARBON ION RADIOTHERAPY FOR UNRESECTABLE RETROPERITONEALSARCOMAS

ITSUKO SERIZAWA, M.D.,* KENJI KAGEI, M.D., PH.D.,* TADASHI KAMADA, M.D., PH.D.,*REIKO IMAI, M.D., PH.D.,* SHINJI SUGAHARA,M.D., PH.D.,* TOHRU OKADA,M.D.,* HIROSHI TSUJI, M.D.,

PH.D.,* HISAO ITO, M.D., PH.D.,y AND HIROHIKO TSUJII, M.D., PH.D.*

*Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan; and yDepartment ofRadiology, Chiba University, Chiba, Japan

Purpose: To evaluate the applicability of carbon ion radiotherapy (CIRT) for unresectable retroperitoneal sarco-mas with regard to normal tissue morbidity and local tumor control.Methods and Materials: From May 1997 to February 2006, 24 patients (17 male and 7 female) with unresectableretroperitoneal sarcoma received CIRT. Age ranged from 16 to 77 years (median, 48.6 years). Of the patients, 16had primary disease and 8 recurrent disease. Histologic diagnoses were as follows: malignant fibrous histiocytomain 6, liposarcoma in 3, malignant peripheral nerve sheath tumor in 3, Ewing/primitive neuroectodermal tumor(PNET) in 2, and miscellaneous in 10 patients. The histologic grades were as follows: Grade 3 in 15, Grade 2-3in 2, Grade 2 in 3, and unknown in 4. Clinical target volumes ranged between 57 cm3 and 1,194 cm3 (median525 cm3). The delivered carbon ion dose ranged from 52.8 to 73.6 GyE in 16 fixed fractions over 4 weeks.Results: The median follow-up was 36 months (range, 6–143 months). The overall survival rates at 2 and 5 yearswere 75% and 50%, respectively. The local control rates at 2 and 5 years were 77% and 69%. No complications ofthe gastrointestinal tract were encountered. No other toxicity greater than Grade 2 was observed.Conclusions: Use of CIRT is suggested to be effective and safe for retroperitoneal sarcomas. The results obtainedwith CIRTwere a good overall survival rate and local control, notwithstanding the fact that most patients were noteligible for surgical resection and had high-grade sarcomas. ! 2009 Elsevier Inc.

Retroperitoneal, Sarcoma, Carbon ion radiotherapy, Particle radiotherapy, Bone and soft tissue sarcomas.

INTRODUCTION

Surgery is the mainstay of treatment for retroperitoneal soft

tissue sarcomas (RPSs). However, complete resection rates

are in the range of 40% to 60%. Because of their anatomic lo-

cation and propensity for spreading extensively, most tumors

are advanced at the time of diagnosis, resulting in difficult re-

section and an inability to achieve negative margins. Many

cases of positive margins or recurrence are detected after

resection (1–3).One-third of retroperitoneal tumors are soft tissue sarco-

mas known to be resistant to radiotherapy (RT), meaning

that high-dose photon beams are necessary to achieve local

control (LC) (4). In contrast to soft tissue sarcomas (STSs)

of the extremity, LC rates greater than 90% are achieved

with a combination of wide local excision and RT (5–7).However, because of the limited radiation tolerance of the

retroperitoneal, abdominal, and pelvic organs, adequate

radiation doses are difficult to deliver, and toxicity can besignificant. Various institutions have advocated preoperativeor postoperative external beam RT, intensity-modulatedradiation therapy (IMRT), intraoperative electron therapy(IORT), and brachytherapy (BT) for the adjunctive treatmentof RPSs, with the goal of improving LC, reducing the likeli-hood of distant metastasis, and improving overall survival(OS). However, the role of systemic therapy also remains con-troversial (8, 9).

Between 1997 and 1999, a Phase I/II dose escalation studyof CIRT trial for bone and soft tissue sarcomas (BSTSs) wasconducted at the National Institute of Radiological Sciences(NIRS) (10, 11). It was concluded that CIRT is an effectivelocal treatment for patients with BSTSs for whom surgical re-section is not a viable option, and that CIRT seems to repre-sent a promising alternative to surgery. There was no case offatal toxicity, and no patient need a colostomy. The morbidityrate of CIRT has so far been quite acceptable. However, in

Reprint requests: Itsuko Serizawa, M.D., Research Center Hospi-tal for Charged Particle Therapy, National Institute of RadiologicalSciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan. Tel:+81-43-251-2111; Fax: +81-43-206-6506; E-mail: s_itsuko@nirs.go.jp

Conflict of interest: none.Received Oct 3, 2008, and in revised form Dec 11, 2008.

Accepted for publication Dec 11, 2008.

1105

Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 4, pp. 1105–1110, 2009Copyright ! 2009 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2008.12.019

Serizawa-et-al:-IJROBP-75:-1105–1110,-2009 Histologic subtype n MFH 6 Liposarcoma 3 MPNST 3 Ewing/PNET 2 Other 10

Histological grade G3 (high grade) 15 G2–3 (high grade) 2 G2 (intermediate) 3 G1 (low grade) 0 Unknown 4 Total 24

Preliminary-results-of-C0ion-RT-alone-in--unresectable-RPS-at-NIRS

JOPYS * J dW W e W aRe O WS

8 a S SO W >) >* >+ >,I W *( , ( (>O W S W OY ( ( ( (

CO S SO W >) >* >+ >,I W ** ) ( (>O W S W OY ( ( ( (ESa Y UW ( - ( (

Serizawa"et"al:"IJROBP"75:"1105–1110,"2009

JOPYS , : YW O W W aRWS S SR� � � � 8 a S o>* CO S o>* �

=W Oa V eSO J SO S Y *%e C: > EJ > EJ ;SO V

>WYPSOa *((* )/ F <9HJh FHJ ,- /( // ( 1 )1 (

=SW )11- *( F <9HJ )1 /* - ( ( ( (

A S *((* *) F <9HJh 9J ,) 0( )- ( )( * /

GS S *((* ** F <9HJ FHJ 0/ 0, ), )( % % (

JfS U *((. *+ F DHJ ), 0( . ( . ( (

:a S aRe *((1 :%W OY S *, // ( ( ( *) (

)/ >WYPSOa C BO > I S YS < S OY *((* kIa UW OY S S W O R ORW VS O e T W O e S S W SOY T W aSO O k 3.-2)+/i),+

*( =SW ;8 : 9M CO WO HD S OY )11- kDO OUS S T S S W SOY O O 2 ; S R S S OYO W W OY SUW OY Y7l 3+)2)*1i)+,

*) A S AA :O :E F IaYYWbO 9 S OY *((* k W WOY S aY T O WOY T S S O WbS Sd S OY%PSO ORWO W VS O e O RS O WbS P O Ve VS O e T S S W SOY O O l 312+,.i+-,

** GS S S 8 ?ORR D> ; VaS A? S OY *((* kK S T W O S O WbS SYS PSO ORW VS O e W VS O OUS S TS S W SOY T W aS O O l 3-*2,.1i,/-

*+ JfS U :M =WbSO V A9 G YS H8 S OY *((. kG S S O WbS ORWO W VS O e cW V SYS WbS R S S OYO W VS O UW OW T S S W SOY O O l 3)(/2+/)i+/1

*-Neurotoxicity:-3-of-the-5-pa,ents-had-neurologic-disabili,es-before-CIRT

Serizawa"et"al:"IJROBP"75:"1105–1110,"2009

Results-of-C0ion-RT-in-RP0STS-at-NIRS-N=24-

-The-50yr-overall-survival-:-50%.

-The-50yr-Local-Control-:-69%.

Serizawa"et"al:"IJROBP"75:"1105–1110,"2009

JOPYS + FbS OYY a bWbOY FI O R Y OY Y C: mW bO W a aRWS

8PP SbWO W 2 9J 5 P O Ve VS O e3 : HJ 5 O P W ORW VS O e3 <9HJ 5 Sd S OY PSO ORWO WVS O e3 FHJ 5 W O S O WbS3 ORWO W VS O e3 E; 5 RS W W 3 F 5 S O W

First author, year Treatment n Resec-

tion (%)

Complete resection

(%)

Microsco-pically

positive margin

(%)

5-y OS (%)

5-y LC (%)

Catton, 1994 (2) Op+EBRT 104 43 36 28 Stoeckle, 2001 (14) Op+EBRT 145 65 49 41 Van Dalen, 2001 (15) Op 142 54 ND ND 32 Lewis, 1998 (4) Op+EBRT 278 67 49 18 54 59

Gronch, 2004 (16) Op+EBRT+IORT 167 88 53 54

Gilbeau, 2002 (17) Op+EBRT 45 38 58 60 40

Krempien, 2006 (18) Op+IORT EBRT 67 31 51 64 40

Youssef, 2002 (19) Op+EBRT BT 60 45 30 56 71

Current study (2009) C-ion RT alone 24 � � � 50 69

Serizawa"et"al:"IJROBP"75:"1105–1110,"2009

Update-Results-of-C0ion-RT-alone-for-RP-and-paracervical-STS-at-NIRS

So4,Tissue,Sarcomas,of,Retroperitoneal,and,Paracervical,region,at,NIRS,(1996.6,�,2012.2,,,n=56)

Age� -14078-y/o��Median-58�-Gender� -M:F=29:27-Previous-Tx� Fresh-case --36-

-----Post0ope-rec-or-meta -20-

Histo0pathology No. MFH 14 Liposarcoma 6 MPNST 5 Synovial-sarcoma 4 Rhabdomyosarcoma 4 Others 23

0 24 48 72 96 1200

20

40

60

80

100

months

Perc

ent s

urvi

val

- - -24mo. -60mo.-Local-Control - -83% -65%-Overall-Survival -65% -42%

Retroperitoneal,and,Paracervical,Sarcomas�,1996.6,��2012.2�n=56,

Local-Control

Overall-Survival

0 24 48 72 96 1200

20

40

60

80

100

prior surgery

only CIRT

monthsP

erce

nt s

urvi

val

�Retroperitoneal-and-Paracervical-Sarcomas-0-Post0ope-Recurrence-vs-Fresh-case-0-

Post0ope-(n=20)-,-Fresh-(n=36) Survival Local-Control

- -36m. -60m.-Post0ope -39% -32%-Fresh - -60% -48%

- -36m. -60m.-Post0ope -75% -45%-Fresh - -73% -73%

Toxici>es,in,Retroperitoneal,and,Paracervical,Sarcomas

-

•  ≧G3-Derma,,s-0%-

•  ≧G2-Myelopathy -5%-(3/56pts)-

•  ≧G3-Intes,nal - -0%-

•  Hydronephrosis- -25%-

- - -(Renal-func,on:-Normal� - -- - - - - - --

(1) 9901-154 PNET/Ewing of the psoas 52M

764361 9901���-145 liposarcoma p/o rec 68F�

spacer"

9901F(2)F145�"liposarcoma"of"the"retroperitoneum""p/o"rec""54�F"

�����

9901F(2)F145�"liposarcoma"of"the"retroperitoneum""p/o"rec""54�F"

9ST S : HJ 8T S : HJ

CR PR SD PD

44y/o, M��MFH

Before 9-yrs

66"

9901-76 LMS of the retroperitoneum 42 M

Actuarial,local,control,rate,according,to,treatment,received,in,RP*STS

=W Oa V STS S S NSO E T O WS -%eSO C:

: YS S H( H) S S W OY S� / O W YS )11)%*((+ 1g*() 0g,/

: YS S H( H) S S W O R ORWO W � 0 S )11+g*((- )+g.( +0g/)

: YS S H( H) S S W O R ORWO W cW V FHJIW RSYO )11+ )11+ )- .(8YS WO *((( *((( +* .*>SW VS *(() *(() ). 0+GS S S *((* *((* 0/ -1B S WS *((. *((. )* )((9OYY *((/ *((- )0 -)

:O P %W HJ OY SE HI *()* -. .-LC"""local"control;"R0/R1"""margin"negaKve/posiKve;"IORT"""intraoperaKve"

Ballo-MT,-et-al:-IJROBP-67:-1580163,-2007

<50%

>50%

Summary: Bone and Soft Tissue Sarcoma

! During 1996 and 2012 at NIRS, C-ion RT was administered to 854 pats with B&S sarcomas including 56 pats with retroperitoneal and paracervical sarcomas, who were considered unfit to surgery, using 64~73.6GyE/16 fr/4wks.

!  In these tumors, C-ion RT as a sole treatment has yielded comparable or even better results as compared to surgery, indicating that C-ion RT could replace surgery in elderly patients and in patients whose function would be greatly reduced if resected..

Role,of,C*ion,RT,in,RP*STS The-results-obtained-with-C0ion-RT-at-NIRS-could-have-shown-overall-survival-and-local-control-rates-comparable-to-surgery-with/without-radia,on,-notwithstanding-the-fact-that-most-pa,ents-were-not-eligible-for-surgical-resec,on-and-had-high0grade-sarcomas.

Thank You

Ion Beams in Biology and Medicine 11th HCPMB-Workshop

Annual conference of the German-Swiss Association for Radiation Protection Joint GAST Conference September 26-29, 2007

KFDA