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SKELETAL OSTEOSARKOMA

Histopatologi:
• Teleangiektasis Osteosarkoma (Osteogenic sarcoma) • Mesenchymal chondrosarkoma
• Paraosteal Osteosarkoma (Osteogenic sarcoma) • Malignant Giant cell tumor
• Chondrosarkoma
Penggolongan Stage (Stadium)
Grade Besar & Letak Keterlibatan
Stadium Histopatologis* Tumor Primer KGB regional Metastasis
Pengobatan
IA G1-G2 T1 N0 M0 LSpS
IB G1-G2 T2 N0 M0 LSS
IIA G3-G4 T1 N0 M0LSpS Adjuvant Kemo
Neoadjuvant Kemo
IIB G3-G4 T2 N0 M0 LSS
Adjuvant Radioterapi
Neoadjuvant Kemo
IIIA G1-G2 Any T N1 M0 LSp/SS
Adjuvant Radioterapi
IIIB G3-G4 Any T N1 M0 Neoadjuvant Kemo
LSp/SS
Adjuvant Radioterapi
IV Any G Any T Any N M1 Paliatif
* Kecuali osteogenic sarcoma. LSpS: Limb Sparing Surgery, LSS: Limb Salvage Surgery
Batasan:
Besar Tumor. Metastasis jauh.
Tx Tumor primer tidak/belum dapat di tentukan Mx Metastasis jauh tidak/belum dapat di tentukan
T0 Tidak/belum jelas ditemui tumor primer M0 Tidak dijumpai metastasis jauh
T1 Terbatas pada cortex M1 Dijumpai metastasis jauh.
T2 Menginvasi jaringan sekitar cortex Grading Histopatologis.
Metastasis KGB regional. Gx Tidak/belum dapat di tentukan
Nx Metastasis KGB regional tidak/belum dapat di G1 Berdifferensiasi baik
tentukan G2 Berdifferensiasi sedang
N0 Tidak dijumpai metastasis pada KGB regional G3 Berdifferensiasi buruk
N1 Dijumpai metastasis pada KGB regional G4 Tidak berdifferensiasi (Anaplastik)

Kemoterapi.
Prabedah: NON TELEANGIEKTATIK OSTEOSARKOMA : Dox-Cis (EOI)
TELEANGIEKTATIK OSTEOSARKOMA: T10
Pascabedah: Grading respons chemotherapy Huvos
Grade Effect
I Sedikit osteoid (< 50%) tumor aselular, nekrosis, dan/atau fibrotik, atau tidak dapat diidentifikasi
efek kemoterapinya
II Sebagian (50-75%) osteoid tumor aselular, nekrosis, dan/atau fibrotik, sebagian lagi dijumpai
kelompokan sel kanker masih viable
III Sebagian besar (75-100%) osteoid tumor aselular, nekrosis, dan/atau fibrotik, hanya sebagian
kecil dan tersebar sel kanker masih viable
IV Seluruh (100%) osteoid tumor aselular, nekrosis, dan/atau fibrotik, tidak dijumpai sel kanker
yang masih viable

1
Neoadjuvant:
NON TELEANGIEKTATIK OSTEOSARKOMA
PROTOKOL DOXOCISP (EOI) UNTUK NON TELEANGIEKTATIK OSTEOSARKOMA PRABEDAH.
HARI KE JAM KE JALUR 1 JALUR 2
0. 12.00 Rehidrasi: Infus D/S minimal 1500 cc
Infus NS (40 gtt/m).
0.00 • Dexametason 10 mg/iv • Navoban 1 amp dalam 100mL NS iv drip
• Avil 1 amp/iv 15-30 menit
Doxorubisin (25 mg/m2) ... mg dalam 100 ml
1.00
1. NS 15 menit, kemudian Bilas
1.30 Infus Manitol 100cc dalam 1 jam
Infus Cisplatin (100mg/m2) .... mg dibagi 3
2.30
dosis tiap dosis dalam 500 ml NS 24 gtt/m
4.00 Jalur 1: Infus D5/W+12,5mEq KCl dan NS +12,5mEq KCl. gantian (28 gtt/m).
UMU tiap 6 jam, target minimal diuresis 100cc/jam.
6.00
Jika < 100 cc/jam Lasix 2 amp/iv
Infus NS (40 gtt/m).
0.00 • Dexametason 10 mg/iv • Navoban 1 amp dalam 100mL NS iv drip
• Avil 1 amp/iv 15-30 menit
Doxorubisin (25 mg/m2) ... mg dalam 100 ml
1.00
2 & 3. NS 15 menit, Bilas dan Emergency
4.00 Jalur 1: Infus D5/W+12,5mEq KCl dan NS +12,5mEq KCl. gantian (40 gtt/m).
UMU tiap 6 jam, target minimal diuresis 100cc/jam.
6.00
Jika < 100 cc/jam Lasix 2 amp/iv
Grading respons:
Huvos I/II
85 106 127
1 22 43 64 71 148 169 190

123 123 123 123 123 1


DD D DD D DD D Bedah DD D DD D Bleo
P P P P P C yclo
Dactinomycin
Skema EOI + T10A
Huvos III/IV
85 106 127

148 169 190

1 22 43 64 71 211 232

1 2 3 1 2 3 1 2 3 1 HdMTX d1,8 HdMTX d1,8


DD D DD D DD D Bedah Bleo FA start d2,9 FA start d2,9
P P P Cyclo D d15,16,17
Dacti
Skema EOI + T10B
Bleomycin : 15mg/m2 bolus
Dactinomycin : 600µg/m2 dalam 100 mL NaCl 30 menit
Cyclophosphamide : 600mg/m2 dalam 250 mL NaCl 60 menit
Doxorubicin : 25 mg/m2 dalam 100 mL NaCl 30 menit
HdMTX : 8-12 gr/m2 dalam 1000mL D5W + 1 mEq/kgBB Bicnat 6 jam

2
Folinic acid : 15 mg/os/6jam sebanyak 10 dosis start 20 jam setelah HdMTX

TELEANGIEKTATIK OSTEOSARKOMA
1 29 36 43 64 71 78 85 99 106 113 120 T10A

T10B
Vinc ristin d1,8,15 Bleo HdMTX d64,71 HdMTX d99,106
Vinc ristin d120
HdMTX d1,8,15,22 Bedah C yc lo Vinc ristin d78,85 Vinc ristin d113
LSpS or Dac ti Doxo d78,79,80 Endo
LSS Prothesis
Protokol T10 (Sloan Kattering)
Vincristin : 2 mg/iv bolus
HdMTX : 8-12 gr/m2 dalam 1000mL D5W + 1 mEq/kgBB Bicnat 6 jam
Folinic acid : 10-15 mg/os/6jam sebanyak 10 dosis start 20 jam setelah HdMTX
Doxorubicin : 25 mg/m2 dalam 100 mL NaCl 30 menit

Bleomycin : 15mg/m2 bolus


Dactinomycin : 600mg/m2 dalam 100 mL NaCl 30 menit
Cyclophosphamide : 600mg/m2 dalam 250 mL NaCl 60 menit

Adjuvant:
Histopatologic grading:
G1-2: EOI + T10A
G3-4: EOI + T10B

Paliatif:
First line: Dox-Cis (EOI)
Second line: I(M)A [Ifosfamide, Mesna, Doxo], (M)AID[Mesna, Doxo, Ifos,
Dacarbazine]
Refractory doxo base: VI(M)E

Relapsed
I(M)EM Relapsed Osteosarcoma Protocol 3-4 week/cycle
Day Line Drug and dose Explanation
Ifosfamide 1 g/m2 + Mesna 1 g/m2 in 500
2
Ifosfamide 3 g/m /d mL
1
d1, 2, 3 Mesna 3 g/m2/d NS carbon covered 8h infusion
(Total 1500 mL NS/day)
2 Etoposide 75 mg/m2/d in 250 mL NS carbon covered 4h infusion
Mesna 1 g/m2 in 500 mL NS 8h infusion
d4 1 Mesna 3 g/m2/d
(Total 1500 mL NS/day)
Methotrexate 4 g/m2 + 1 mEq/kgBB Bicnat
in 250 mL NS (Σ volume ± 500 mL) 12h
d15 1 Methotrexate 8 g/m2/d
infusion
(Total 1000 mL NS/day)
d15*,16,17, Lecovorin15 mg/6h * First dose 20h MTX d15,
oral
18 (Total 10 doses) next dose 0h d16 every 6h
(Michelagnoli et al, Br J Cancer 1999;79(7-8):1174-78)

3
SARKOMA JARINGAN LUNAK
Penggolongan Stage (Stadium)
Grade Besar & Letak Keterlibatan
Stadium Histopatologis Tumor Primer KGB regional Metastasis
IA G1-G2 T1a N0 M0
IB G1-G2 T1b -T2a N0 M0
IIA G1-G2 T2b N0 M0
IIB G3-G4 T1a N0 M0
IIIA G3-G4 T1b -T2a N0 M0
IIIB G3-G4 T2b N0 M0
IV Any G Any T N1 M0
Any N M1
Batasan:
Besar Tumor.
Tx Tumor primer tidak/belum dapat di tentukan
T0 Tidak/belum jelas ditemui tumor primer
T1 Dimensi terbesar tumor ≤ 5 cm
T2 Dimensi terbesar tumor > 5 cm
Sub T:
a. Tumor superfisial belum menembus fascia, atau
Tumor pada ekstremitas tidak/belum menginvasi pembuluh darah besar.
b. Tumor dalam:
• Intra peritoneal,
• Intra thorax,
• Tumor meng invasi ke pembuluh darah besar, atau
• Head & Neck.
Metastasis KGB regional.
Nx Metastasis KGB regional tidak/belum dapat di tentukan
N0 Tidak dijumpai metastasis pada KGB regional
N1 Dijumpai metastasis pada KGB regional
Metastasis jauh. Grading Histopatologis.
Mx Metastasis jauh tidak/belum dapat di tentukan Gx Tidak/belum dapat di tentukan
M0 Tidak dijumpai metastasis jauh G1 Berdifferensiasi baik
M1 Dijumpai metastasis jauh. G2 Berdifferensiasi sedang
G3 Berdifferensiasi buruk
G4 Tidak berdifferensiasi (Anaplastik)
Jenis Soft tissue sarcoma
Jaringan lunak Jaringan tulang
Malignant Fibro Histiocytoma Non Skeletal Osteogenic sarcoma
Liposarcoma Chondrosarcoma
Fibrosarcoma Ewing
Synovial sarcoma
Neurofibrosarcoma
Malignant Schwanoma
Hemangiosarcoma
Leiomyosarcoma
Rhabdomyosarcoma

4
Rhabdomyosarcoma
a. Embryonal rhabdomyosarcoma
b. Botryoid rhabdomyosarcoma
c. Spindle cell rhabdomyosarcoma
d. Alveolar rhabdomyosarcoma
e. Pleomorphic rhabdomyosarcoma

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Tumor Histology Chromosomal Alteration Involved Gene(s) Frequency Reference
-------------------------------------------------------------------------------------------------------------------------------------------
Embryonal rhabdomyosarcoma Trisomy 2, trisomy 8 Unknown Rare 455,456
Alveolar rhabdomyosarcoma t(2;13)(q35;q14) PAX3-FKHR ± 70% 439
t(1;13)(p36;q14) PAX7-FKHR ± 15% 73,439
-------------------------------------------------------------------------------------------------------------------------------------------

PROTOKOL CYVADIC SOFT TISSUE SARCOMA


HARI KE JAM KE JALUR 1 JALUR 2
0. Infus NS (28 gtt/m). Navoban 1 amp dalam 100mL NS iv drip 15-30 menit
• Dexametason 10
mg/iv
• Avil 1 amp/iv
2. Vinkristin (1 mg/m2) ……. mg dalam 100 ml NS 15 menit,
kemudian Bilas dan Emergency
1 4. Doxorubisin (50 mg/m2) .... mg dalam 100 ml NS 15 menit,
kemudian Bilas dan Emergency
6. Infus D5/W (28 gtt/m). Dacarbazin (250 mg/m2) .…… mg dalam 250 ml NS 1 jam,
kemudian Bilas dan Emergency
8. Siklofosfamid (500 mg/m2) ... mg dalam 250 ml NS 2 jam,
kemudian Bilas dan Emergency
12. Selanjutnya infus NS:D5/W
gantian (28 gtt/m).
0. Infus NS (28 gtt/m). Navoban 1 amp dalam 100mL NS iv drip 15-30 menit
2,3, & 4 2. Dacarbazin (250 mg/m2) ..... mg dalam 250 ml NS 1 jam,
kemudian Bilas dan Emergency
6. Selanjutnya infus NS:D5/W
gantian (28 gtt/m).
0. Infus NaCl 0,9% (28 gtt/m). Navoban 1 amp dalam 100mL NS iv drip 15-30 menit
2. Vinkristin (1 mg/m2) ….. mg dalam 100 ml NS 15 menit,
5 kemudian Bilas dan Emergency
4. Dacarbazin (250 mg/m2) …... mg dalam 250 ml NS 1 jam,
kemudian Bilas dan Emergency
6. Selanjutnya infus NS:D5/W
gantian (28 gtt/m).

Definitive Radiation
Surgery remains the main treatment for patients with sarcoma of the extremity, and every effort
should be made to attempt resection. However, in some patients with unresectable disease definitive
radiation could be considered due to medical reasons or to achieve some palliation. Since sarcoma may
be radiocurable in terms of cell killing but not radioresponsive in terms of shrinkage of the mass, this can
be perplexing, as such masses could give the false impression that little has been accomplished,
whereas in reality the mass is mainly made up of sterilized tumor cells and debris. Tepper and Suit
reported on 51 patients treated with definitive photon beam irradiation to a total dose of 64 to 66 Gy. The
5-year local control and survival rate were 33% and 25%, respectively. Local control was better for
tumors less than 5 cm (87.5%) than in tumors 5 to 10 cm (53%) or greater than 10 cm (30%). [ref: 225]
Slater et al. showed similar findings in 57 patients treated with definitive photon irradiation to 44 to 88 Gy.
The 5-year local control was 28%.[ref: 226]

5
Other investigators have looked at using neutron radiotherapy either alone or in combination with
photon beam radiation. Schwarz et al. reviewed the European experience with such an approach and
reported a local control rate of 50%, but the rate of severe complications ranged from 6.6% when neutron
therapy was used as a boost to 50% when used alone. [ref: 228]

Radiation and Chemotherapy


The purpose of combined radiation and chemotherapy treatment is not to decrease the dose of
radiation to gain the same effect, but rather to increase the therapeutic index. This may be achieved
using techniques that take advantage of the different mechanisms of action of systemic chemotherapy
and regional irradiation. A second way to increase the therapeutic index is to use drugs that specifically
affect tumor response to radiation; the most exciting of these are the hypoxic sensitizers, because they
affect hypoxic cells that usually are restricted to tumors. Chemotherapeutic agents that directly modify the
radiation survival curve may be used. A good example of this is the use of dactinomycin in the treatment
of childhood rhabdomyo-sarcoma or Wilms' tumor. Dactinomycin is composed of a planar tricyclic ring
chromophore (phenoxazone) to which two identical cyclic polypeptides are attached. [ref: 175] The
compound binds to DNA by intercalation, depending on a specific interaction between the polypeptide
chains and deoxyguanosine. This interaction blocks the ability of DNA to act as a template for RNA and
DNA synthesis in a concentration-dependent manner. Low drug concentrations inhibit RNA synthesis
more than higher drug concentrations, which block both RNA and DNA syntheses. Dactinomycin can also
cause topoisomerase-mediated single-strand breaks in DNA, although the contribution of these
breaks to cytotoxicity is unclear. [ref: 176] In vitro studies suggest that concomitant actinomycin D and
hyperthermia (e.g., 42o or 43oC) resulted in an increased uptake and prolonged retention of actinomycin
D.[ref: 177] More recently, hyperfractionated photon radiation was combined with intravenous
iododeoxyuridine as a radiosensitizer. Goffman et al. reported on 36 patients treated in this fashion, and
with a median follow-up of 4 years the local control rate was 60%. [ref: 227] Subsequent pilot studies of
concurrent chemoradiation by FA 50 mg/m2 + FU 500 mg/m2 + Campto 85 mg/m2 weekly followed
by 300 cGy/day 5 days/week total dose of 6400 to 6600 cGy currently being evaluated for responses.

Chemotherapy
Embryonal RMS of the trunk should be treated using the chemotherapy regimens appropriate for the
clinical group.
 Group I tumors are treated with the combination of vincristine and dactinomycin, [ref:
263,265] wherea
 Groups II, III, and IV are managed with the combination of VAC. [ref: 263,265]
 Primary tumors of the trunk frequently consist of alveolar elements. [ref: 285] As in other
sites, alveolar tumors in the trunk do not respond to chemotherapy as favorably as embryonal
disease.
 Children with intermediate- or high-risk disease arising in these sites are currently being
evaluated for response to VAC plus one of the camptothecin analogues.
Survival for metastatic (stage IV) patients has only marginally improved from 20% to 32% since the
inception of the IRS in 1972. In an effort to improve survival in this very high-risk subset of children, a
series of phase II window studies have been undertaken. Patients with metastatic RMS are now being
treated with an induction regimen that combines vincristine with irinotecan. Like topotecan, irinotecan is a
camptothecin analogue that exerts its cytotoxic effect by inhibition of topoisomerase I. Irinotecan has
demonstrated impressive antitumor activity in preclinical studies with murine xenografts. Subsequent pilot
studies for metastatic patients may revisit the therapeutic potential of anthracyclines in the form of Doxil,
a liposomally encapsulated analogue of doxorubicin, currently in phase I studies. It is hoped that the
liposomal delivery system will minimize cardiotoxicity, permitting more dose-intensive application of
anthracyclines to sarcoma therapy.

6
Overall distribution of patients in major Intergroup Rhabdomyosarcoma Study clinical trials according to
clinical group and primary site. (From ref. 241, with permission.)

MAID
Day Tim Drug and dose Explanation
Line
e
1 2 Doxorubin 30 mg/d In 50 mL NS 30min
Ifosfamide 1.25 g + Mesna 1.25 g in
Ifosfamide 3.75 g/d 500 mL NS carbon covered 8h
d1, 2, 3 1
2 Mesna 3.75 g/d infusion
(Total 1500 mL NS/day)
2 Dacarbazin 450 mg/d in 500 mL NaCl 0,9% 24h infusion
1 Mesna 1.5 g in 500 mL NS 12h
d4 1 Mesna 1.5 g
infusion