non metastatic osteosarcoma. experience at skmch & rc alia zaidi, ahsan shamim, wasila shamim...

NON METASTATIC NON METASTATIC OSTEOSARCOMA. EXPERIENCE OSTEOSARCOMA. EXPERIENCE

AT SKMCH & RC AT SKMCH & RC

ALIA ZAIDI, AHSAN SHAMIM, WASILA SHAMIMALIA ZAIDI, AHSAN SHAMIM, WASILA SHAMIM

SHAUKAT KHANUM MEMORIAL CANCER HOSPITAL AND SHAUKAT KHANUM MEMORIAL CANCER HOSPITAL AND RESEARCH CENTRERESEARCH CENTRE

NON METASTATIC NON METASTATIC OSTEOSARCOMA. EXPERIENCE OSTEOSARCOMA. EXPERIENCE

AT SKMCH & RC AT SKMCH & RC

ALIA ZAIDI, AHSAN SHAMIM, WASILA SHAMIMALIA ZAIDI, AHSAN SHAMIM, WASILA SHAMIM

SHAUKAT KHANUM MEMORIAL CANCER HOSPITAL AND SHAUKAT KHANUM MEMORIAL CANCER HOSPITAL AND RESEARCH CENTRERESEARCH CENTRE

BACKGROUNDBACKGROUND THE ROLE OF CHEMOTHERAPY IN THE THE ROLE OF CHEMOTHERAPY IN THE

TREATMENT OF OSTEOSARCOMA IS NOW TREATMENT OF OSTEOSARCOMA IS NOW WELL ESTABLISHED.WELL ESTABLISHED.

MOST CENTRES REPORT AN MOST CENTRES REPORT AN EFS > 60%EFS > 60% AND AND OS >70%OS >70% FOR NON-METASTATIC , EXTREMITY FOR NON-METASTATIC , EXTREMITY OSTEOSARCOMA. OSTEOSARCOMA.

THE PURPOSE OF THIS STUDY WAS TO THE PURPOSE OF THIS STUDY WAS TO ANALYZE TREATMENT OUTCOME FOR ANALYZE TREATMENT OUTCOME FOR OSTEOSARCOMA AT OUR HOSPITAL.OSTEOSARCOMA AT OUR HOSPITAL.

BETWEEN DECEMBER1994 AND APRIL 2004 , BETWEEN DECEMBER1994 AND APRIL 2004 , 278 PATIENTS <30 YRS AGE WERE 278 PATIENTS <30 YRS AGE WERE REGISTERED AT SKM WITH BONE TUMORS. OF REGISTERED AT SKM WITH BONE TUMORS. OF THESE 134 (48%) HAD OSTEOSARCOMA. THESE 134 (48%) HAD OSTEOSARCOMA.

MATERIALS AND METHODSMATERIALS AND METHODS

A RETROSPECTIVE OBSERVATIONAL STUDY.A RETROSPECTIVE OBSERVATIONAL STUDY.

INCLUSION CRITERIA:INCLUSION CRITERIA: INCLUDED ALL PATIENTS 30 YEARS OF AGE INCLUDED ALL PATIENTS 30 YEARS OF AGE AND YOUNGER WITH BIOPSY PROVEN AND YOUNGER WITH BIOPSY PROVEN OSTEOSARCOMA, REGISTERED AT SKM OSTEOSARCOMA, REGISTERED AT SKM BETWEEN 29/12/94 AND 30/04/04.BETWEEN 29/12/94 AND 30/04/04.

EXCLUSION CRITERIA EXCLUSION CRITERIA METASTATIC AT PRESENTATION. METASTATIC AT PRESENTATION. DID NOT COMPLETE TREATMENT AT DID NOT COMPLETE TREATMENT AT SKM.SKM.

MATERIALS AND METHODSMATERIALS AND METHODS

DATA COLLECTIONDATA COLLECTION INFORMATION WAS EXTRACTED FROM INFORMATION WAS EXTRACTED FROM

PATIENTS’ MEDICAL RECORDS.PATIENTS’ MEDICAL RECORDS. EVENT FREE SURVIVAL (EFS) WAS EVENT FREE SURVIVAL (EFS) WAS

CALCULATED FROM THE DATE OF CALCULATED FROM THE DATE OF DEFINITIVE SURGERY TO THE DATE OF DEFINITIVE SURGERY TO THE DATE OF RELAPSE, PROGRESSION, DEATH OR LAST RELAPSE, PROGRESSION, DEATH OR LAST FOLLOW UP. FOLLOW UP.

OVERALL SURVIVAL (OS) WAS OVERALL SURVIVAL (OS) WAS CALCULATED FROM THE DATE OF CALCULATED FROM THE DATE OF DIAGNOSIS TO DEATH OR LAST FOLLOW DIAGNOSIS TO DEATH OR LAST FOLLOW UP.UP.

STATISTICSSTATISTICS

EFS AND OS CURVES DERIVED EFS AND OS CURVES DERIVED USING THE ACTUARIAL LIFE METHOD USING THE ACTUARIAL LIFE METHOD ON THE SPSS STATISTICAL ON THE SPSS STATISTICAL PACKAGEPACKAGE..

TREATMENT OUTLINETREATMENT OUTLINE

NEOADJUVANT CHEMOTHERAPYNEOADJUVANT CHEMOTHERAPY

SURGERYSURGERY

ADJUVANT CHEMOTHERAPYADJUVANT CHEMOTHERAPY

FIRST LINE CHEMOTHERAPYFIRST LINE CHEMOTHERAPY

REGIMEN 1 :REGIMEN 1 :

CISPLATINCISPLATIN (100mg/m2 24-hour infusion) (100mg/m2 24-hour infusion) ADRIAMYCIN ADRIAMYCIN (25mg/m2 iv daily D1-D3 ). (25mg/m2 iv daily D1-D3 ).

TOTAL 6 CYCLES : 2 NEOADJUVANT & TOTAL 6 CYCLES : 2 NEOADJUVANT & 4 ADJUVANT4 ADJUVANT

FIRST LINE CHEMOTHERAPYFIRST LINE CHEMOTHERAPY

REGIMEN 2 :REGIMEN 2 :

CISPLATINCISPLATIN (100mg/m2 24-hour infusion) (100mg/m2 24-hour infusion) ADRIAMYCINADRIAMYCIN (25mg/m2 iv daily D1-D3 ). (25mg/m2 iv daily D1-D3 ). HDHD METHOTREXATEMETHOTREXATE (8gm/M2 for >12 years (8gm/M2 for >12 years

age & 12gm/M2 for <12 years) given on D22 age & 12gm/M2 for <12 years) given on D22 and D29 of each cycleand D29 of each cycle

TOTAL 6 CYCLES : 2 NEOADJUVANT & TOTAL 6 CYCLES : 2 NEOADJUVANT & 4 ADJUVANT4 ADJUVANT

SECOND LINE CHEMOTHERAPY SECOND LINE CHEMOTHERAPY

IFOSFAMIDEIFOSFAMIDE : : 3gm/M2 D1-D33gm/M2 D1-D3

ETOPOSIDEETOPOSIDE: 200mg/M2 D1- D3: 200mg/M2 D1- D3 HD METHOTREXATEHD METHOTREXATE : 8 – 12 gm/M2 D14 of : 8 – 12 gm/M2 D14 of each cycle.each cycle.

SURGERYSURGERY

AMPUTATIONAMPUTATION

LIMB SALVAGELIMB SALVAGE

RESULTSRESULTS

TOTAL PATIENTSTOTAL PATIENTS =134=134

PATIENTS EXCLUDEDPATIENTS EXCLUDED = 71= 71• METASTATICMETASTATIC = 35= 35• INCOMPLETE TREATMENT= 36INCOMPLETE TREATMENT= 36

ELIGIBLE PATIENTSELIGIBLE PATIENTS = 63= 63

RESULTSRESULTS

MEAN AGE=15.4 YEARSMEAN AGE=15.4 YEARS

AGE RANGE=8–28 YEARSAGE RANGE=8–28 YEARS

77.8% WERE77.8% WERE

<18 YEARS OF AGE <18 YEARS OF AGE

MALE =41MALE =41FEMALE =22FEMALE =22M : F =1.9 : 1M : F =1.9 : 1

Age (years)

27.525.022.520.017.515.012.510.07.5

Fre

quen

cy

20

10

0

Std. Dev = 4.34

Mean = 15.4

N = 63.00

SITE OF TUMOUR SITE OF TUMOUR SITE FREQUENCY PERCENTAGE

DISTAL FEMUR 29 46.0

PROXIMAL TIBIA 13 20.6

PROXIMAL HUMERUS 6 9.5

FIBULA 4 6.4

DISTAL TIBIA 3 4.8

FEMORAL DIAPHYSIS 3 4.8

PROXIMAL FEMUR 2 3.2

TIBIAL DIAPHYSIS 1 1.6

PROXIMAL ULNA 1 1.6

RIBS 1 1.6

TOTAL 63 100.0

RESULTSRESULTSCHEMOTHERAPYCHEMOTHERAPY

NEO-ADJUVANTNEO-ADJUVANTCISPLATIN + ADRIAMYCINCISPLATIN + ADRIAMYCIN N = 30N = 30CISPLATIN + ADRIAMYCIN + HD MTXCISPLATIN + ADRIAMYCIN + HD MTX N = 20N = 20NONENONE N = 13N = 13

ADJUVANTADJUVANTCISPLATIN + ADRIAMYCINCISPLATIN + ADRIAMYCIN N = 33N = 33

CISPLATIN + ADRIAMYCIN + HD MTXCISPLATIN + ADRIAMYCIN + HD MTX N = 30N = 30(SECOND LINE CHEMOTHERAPY)(SECOND LINE CHEMOTHERAPY) N = 12N = 12

NATURE OF SURGERYNATURE OF SURGERY

AmputationAmputation == 44 of 63 (70%)44 of 63 (70%)

Limb salvageLimb salvage == 19 of 63 (30%)19 of 63 (30%)

LIMB SALVAGE PROCEDURE LIMB SALVAGE PROCEDURE

RESECTION ARTHRODESIS RESECTION ARTHRODESIS

OF KNEE = OF KNEE = 88

LIMB SALVAGE PROCEDURE LIMB SALVAGE PROCEDURE

DIAPHYSEAL DIAPHYSEAL LESIONS-LESIONS-

SEGMENTAL SEGMENTAL RESECTION AND RESECTION AND

RECONSTRUCTION RECONSTRUCTION

= = 44

LIMB SALVAGE PROCEDURE LIMB SALVAGE PROCEDURE

TICKHOFF-LINBERG TICKHOFF-LINBERG RESECTION OF THE RESECTION OF THE

SHOULDERSHOULDER = = 44

LIMB SALVAGE PROCEDURE LIMB SALVAGE PROCEDURE

ENNEKING ENNEKING ARTHRODESIS ARTHRODESIS

SHOULDERSHOULDER = = 11

LIMB SALVAGE PROCEDURE LIMB SALVAGE PROCEDURE

VAN NES VAN NES

ROTATIONPLASTYROTATIONPLASTY = = 11

LIMB SALVAGE PROCEDURE LIMB SALVAGE PROCEDURE

• ILIZAROV ILIZAROV

RECONTRUCTIONRECONTRUCTION = = 11

COMPLICATIONS OF TREATMENTCOMPLICATIONS OF TREATMENT

SERIOUS INFECTIONSSERIOUS INFECTIONSHEP. B WITH HEPATIC ENCEPHALOPATHY= 4 (6.3%)HEP. B WITH HEPATIC ENCEPHALOPATHY= 4 (6.3%)

GRAM NEGATIVE SEPTICAEMIA = 6 (9.5%)GRAM NEGATIVE SEPTICAEMIA = 6 (9.5%)

FUNGAL PNEUMONIA = 2 (3.2%)FUNGAL PNEUMONIA = 2 (3.2%)

CHEMOTHERAPY TOXICITYCHEMOTHERAPY TOXICITYCISPLATIN NEUROTOXICITY = 1 (1.5%)CISPLATIN NEUROTOXICITY = 1 (1.5%)

METHOTREXATE NEPHROTOXICITY = 2 (3.2%)METHOTREXATE NEPHROTOXICITY = 2 (3.2%)

ADRIAMYCIN CARDIOTOXICITY = 1 (1.5%)ADRIAMYCIN CARDIOTOXICITY = 1 (1.5%)

PSYCHOLOGICAL COMPLICATIONSPSYCHOLOGICAL COMPLICATIONSMAJOR DEPRESSION = 6 (9.5%)MAJOR DEPRESSION = 6 (9.5%)

COMPLICATIONS OF LIMB SALVAGE COMPLICATIONS OF LIMB SALVAGE SURGERYSURGERY

IMPLANT FAILURE REQUIRING REVISION IMPLANT FAILURE REQUIRING REVISION SURGERY 1 (5.2%)SURGERY 1 (5.2%)

IMPLANT EXPOSURE REQUIRING IMPLANT EXPOSURE REQUIRING SECONDARY PLASTIC SURGICAL SECONDARY PLASTIC SURGICAL RECONSTRUCTION 1 (5.2%)RECONSTRUCTION 1 (5.2%)

FOLLOWUPFOLLOWUP

MEAN FOLLOWUP WAS 32 MEAN FOLLOWUP WAS 32 26 26 months (Mean months (Mean 1SD) 1SD)

RANGE 3.6 TO 98.5 months RANGE 3.6 TO 98.5 months

OVERALL SURVIVALOVERALL SURVIVAL

Overall survival interval in months

100806040200

Su

rviv

al r

ate

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

DEATH2 * LOST Crosstabulation

Count

34 10 44

10 9 19

44 19 63

no

yes

DEATH2

Total

no yes

LOST

Total

60.4% of the patients were alive at 5 YEARS

EVENT FREE SURVIVALEVENT FREE SURVIVAL

Event free survival interval in months

100806040200

Su

rviv

al r

ate

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

.0

40% were event free at 5YEARS

EVENT * LOST Crosstabulation

Count

29 6 35

15 13 28

44 19 63

N

Y

EVENT

Total

no yes

LOST

Total

EFS ACCORDING TO THERAPY –RELATED EFS ACCORDING TO THERAPY –RELATED VARIABLESVARIABLES

Event free survival interval in months

100806040200

Su

rviv

al ra

te

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

.0

Necrosis

>90%

<90%

%age Necrosis%age Necrosis

<90% =44

>90% = 19

(P=0.8633)

EFS ACCORDING TO THERAPY –RELATED EFS ACCORDING TO THERAPY –RELATED VARIABLES VARIABLES

Event free survival interval in months

100806040200

Su

rviv

al r

ate

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

.0

Amputation/Salvage

Limb salvage

Amputation

Amputation Vs Limb SalvageAmputation Vs Limb Salvage

Limb salvage=19

Amputation = 44

(P =0.1895)

RESULTS SUMMARY RESULTS SUMMARY

OVERALL SURVIVAL 60.4% AT 5YRS.OVERALL SURVIVAL 60.4% AT 5YRS.EVENT FREE SURVIVAL 40% AT 5YRS.EVENT FREE SURVIVAL 40% AT 5YRS.NO OS DIFFERENCE BETWEEN GOOD NO OS DIFFERENCE BETWEEN GOOD AND BAD RESPONDERS TO INITIAL AND BAD RESPONDERS TO INITIAL CHEMOTHERAPY.CHEMOTHERAPY.NO OS DIFFERENCE BETWEEN LIMB NO OS DIFFERENCE BETWEEN LIMB SALVAGE AND ABLATION. SALVAGE AND ABLATION. TREATMENT WAS GENERALLY WELL TREATMENT WAS GENERALLY WELL TOLERATED.TOLERATED.

Literature ReviewLiterature Review

Sr. noSr. no JournalJournal AuthorAuthor Pat. No.Pat. No. F/upF/up EFS%EFS% OS%OS%

11 Ann of Oncol Ann of Oncol 8:765-771,19978:765-771,1997

Ferrari et alFerrari et al 127127 12 yrs12 yrs 46%46% 53%53%

22 Clin Ortho & Clin Ortho & Related Research Related Research 358:120-127,1999358:120-127,1999

Sluga et alSluga et al 133133 5 yrs5 yrs 67%67% 70%70%

33 J Clin Oncol J Clin Oncol 18:4016-4027 ,18:4016-4027 ,

20002000

Bacci et alBacci et al 164164 5 yrs5 yrs 63%63% 75%75%

44 The Oncologist, The Oncologist, 9:422-441, 2004.9:422-441, 2004.

Marina et alMarina et al Review Review articlearticle

5 yrs5 yrs

10 yrs10 yrs

74%74%

71%71%

DISCUSSIONDISCUSSION

LATE PRESENTATIONLATE PRESENTATION HIGH PERCENTAGE OF MACROMETASTASES HIGH PERCENTAGE OF MACROMETASTASES

AT PRESENTATION (35 OF 134 = 26%).AT PRESENTATION (35 OF 134 = 26%).LARGE NUMBER PATIENTS PRESENTING WITH LARGE NUMBER PATIENTS PRESENTING WITH

HUGE FUNGATING TUMOURS REQUIRING HUGE FUNGATING TUMOURS REQUIRING UPFRONT AMPUTATION.UPFRONT AMPUTATION.

DISCUSSIONDISCUSSION

LACK OF EDUCATION & AWARENESS LACK OF EDUCATION & AWARENESS HIGH TENDENCY FOR FAMILIES TO HIGH TENDENCY FOR FAMILIES TO

DISCONTINUE TREATMENT MIDWAY.DISCONTINUE TREATMENT MIDWAY. FAILURE TO CONTINUE REGULAR FOLLOW FAILURE TO CONTINUE REGULAR FOLLOW

UP IF THE PATIENT IS ALRIGHT POST UP IF THE PATIENT IS ALRIGHT POST TREATMENT.TREATMENT.

DISCUSSIONDISCUSSION

HIGH SYSTEMIC INFECTION RATE AND CO-HIGH SYSTEMIC INFECTION RATE AND CO-MORBIDITYMORBIDITY

6 DEATHS (31.5%) WERE DUE TO INFECTIONS 6 DEATHS (31.5%) WERE DUE TO INFECTIONS

HEPATITIS B WITH HEPATIC HEPATITIS B WITH HEPATIC

ENCEPHALOPATHY = 4 ENCEPHALOPATHY = 4

SEPTIC SHOCK = 1SEPTIC SHOCK = 1

FUNGAL PNEUMONIA = 1FUNGAL PNEUMONIA = 1

DISCUSSIONDISCUSSION

POSSIBILITY OF BIOLOGICALLY AGGRESSIVE POSSIBILITY OF BIOLOGICALLY AGGRESSIVE DISEASE?DISEASE?

44 OF 63 (70%) HAD <90% POST 44 OF 63 (70%) HAD <90% POST CHEMOTHERAPY NECROSIS.CHEMOTHERAPY NECROSIS.

4 OF 63 (6.3%) HAD DIAPHYSEAL LESIONS.4 OF 63 (6.3%) HAD DIAPHYSEAL LESIONS.

CONCLUSIONSCONCLUSIONS

• OUR RESULTS ARE COMPARABLE TO INTERNATIONAL OUR RESULTS ARE COMPARABLE TO INTERNATIONAL FIGURES THOUGH A MUCH LONGER FOLLOW UP (AT LEAST FIGURES THOUGH A MUCH LONGER FOLLOW UP (AT LEAST 10 YEARS) IS REQUIRED TO GET A MORE ACCURATE 10 YEARS) IS REQUIRED TO GET A MORE ACCURATE PICTURE.PICTURE.

• PATIENTS NEED TO BE STUDIED PROSPECTIVELY TO PATIENTS NEED TO BE STUDIED PROSPECTIVELY TO ENSURE MORE RELIABLE DATA.ENSURE MORE RELIABLE DATA.

• WE NEED TO ORGANIZE EDUCATIONAL CAMPAIGNS TO WE NEED TO ORGANIZE EDUCATIONAL CAMPAIGNS TO IMPROVE PUBLIC AND HEATH PERSONNEL AWARENESS IMPROVE PUBLIC AND HEATH PERSONNEL AWARENESS ABOUT TREATABLE NATURE OF THIS DISEASE IF CAUGHT ABOUT TREATABLE NATURE OF THIS DISEASE IF CAUGHT EARLY. EARLY.

• DESPITE LIMITATIONS OF WORKING IN A THIRD WORLD DESPITE LIMITATIONS OF WORKING IN A THIRD WORLD

TERTIARY CARE CENTRE, OUR PRELIMINARY RESULTS OF TERTIARY CARE CENTRE, OUR PRELIMINARY RESULTS OF LIMB SALVAGE SURGERY ARE HEARTENING (30%, NO LIMB SALVAGE SURGERY ARE HEARTENING (30%, NO STATISTICALLY SIGNIFICANT DIFFERENCE IN OUTCOME STATISTICALLY SIGNIFICANT DIFFERENCE IN OUTCOME COMPARED TO ABLATIVE SURGERY).COMPARED TO ABLATIVE SURGERY).