chou aj, merola pr, vyas y, wexler l, gorlick r, laquaglia m, healey j, huvos a, meyers pa

Treatment of Relapsed Treatment of Relapsed Osteosarcoma After Contemporary Osteosarcoma After Contemporary

Therapy: The Memorial Sloan-Therapy: The Memorial Sloan-Kettering ExperienceKettering Experience

Chou AJ, Merola PR, Vyas Y, Wexler L, Chou AJ, Merola PR, Vyas Y, Wexler L,

Gorlick R, LaQuaglia M, Healey J, Huvos A, Gorlick R, LaQuaglia M, Healey J, Huvos A, Meyers PAMeyers PA

Scope of the ProblemScope of the Problem

> 400 new pediatric cases of OS / year> 400 new pediatric cases of OS / year survival for localized disease > 70%survival for localized disease > 70% < 20% for recurrent disease< 20% for recurrent disease optimal strategy for recurrent disease is optimal strategy for recurrent disease is

undefinedundefined

Treatment for Recurrent OSTreatment for Recurrent OS

31.6% 31.6% (3y) (3y) ––23.7 % 23.7 % (5y)(5y)

Surgery +/Surgery +/ --

IFOS / IFOS / EtopEtop

CDDP/DOX CDDP/DOX ++IFOS or HD MTXIFOS or HD MTX

CDDP/CDDP/ Doxox/ IFOS/EtopDoxox/ IFOS/Etop

333319791979--19981998DuffaudDuffaud et alet al

20032003

28% (4y)28% (4y)7% (4y)7% (4y)Surgery +/Surgery +/ --


IFOS / IFOS / EtopEtop / Carbo/ Carbo

595919901990--20002000Hawkins et alHawkins et al

20032003


HD IFOSHD IFOS

BCDBCD

CDDP/CDDP/ EtopEtop

CyclphosCyclphos / / EtopEtop

IFOSIFOS

16216219861986--19951995Ferrari et alFerrari et al

20032003

24& (5y)24& (5y)--Surgery + RTSurgery + RT

Surgery + Surgery + ChemoChemo + RT+ RT

ChemoChemo + RT+ RT

RTRT

NoneNone

606019751975--19931993SaeterSaeter et alet al

19941994


VindesinVindesin/ IFOS/CDDP/IFOS/CDDP

CDDPCDDP

Hd MTXHd MTX

IFOS/IFOS/ EtopEtop

CarboCarbo

HD MTX/HD MTX/ IfosIfos

424219811981--19931993TaboneTabone et alet al

19941994

OSOSDFSDFSTx for RecurrenceTx for Recurrence#Pt#PtYearsYearsStudyStudy

31.6% 31.6% (3y) (3y) ––23.7 % 23.7 % (5y)(5y)

Surgery +/Surgery +/ --


CDDP/DOX CDDP/DOX ++IFOS or HD MTXIFOS or HD MTX

CDDP/CDDP/ Doxox/ IFOS/EtopDoxox/ IFOS/Etop

333319791979--19981998DuffaudDuffaud et alet al

20032003



IFOS / IFOS / EtopEtop / Carbo/ Carbo

595919901990--20002000Hawkins et alHawkins et al

20032003


HD IFOSHD IFOS

BCDBCD

CDDP/CDDP/ EtopEtop

CyclphosCyclphos / / EtopEtop

IFOSIFOS

16216219861986--19951995Ferrari et alFerrari et al

20032003

24& (5y)24& (5y)--Surgery + RTSurgery + RT

Surgery + Surgery + ChemoChemo + RT+ RT

ChemoChemo + RT+ RT

RTRT

NoneNone

606019751975--19931993SaeterSaeter et alet al

19941994


VindesinVindesin/ IFOS/CDDP/IFOS/CDDP

CDDPCDDP

Hd MTXHd MTX

IFOS/IFOS/ EtopEtop

CarboCarbo

HD MTX/HD MTX/ IfosIfos

424219811981--19931993TaboneTabone et alet al

19941994

OSOSDFSDFSTx for RecurrenceTx for Recurrence#Pt#PtYearsYearsStudyStudy

Study ObjectiveStudy Objective

To determine the outcome for patients To determine the outcome for patients with recurrent OS who were treated at with recurrent OS who were treated at MSKCC after 1MSKCC after 1stst relapse (R1) relapse (R1)

Study DescriptionStudy Description

Retrospective chart reviewRetrospective chart review Eligibility criteria:Eligibility criteria:

biopsy proven high grade osteosarcomabiopsy proven high grade osteosarcoma documented CR after receiving “contemporary” therapy = documented CR after receiving “contemporary” therapy =

surgery + chemotherapy [HD MTX, CDDP, DOX, surgery + chemotherapy [HD MTX, CDDP, DOX, ++ IFOS] IFOS] tx for R1 at MSKCC after 1990tx for R1 at MSKCC after 1990

Definitions:Definitions: RFS = time from CR2 to either R2 or death from any RFS = time from CR2 to either R2 or death from any

causecause RFS=0 if never achieved CR2RFS=0 if never achieved CR2

Overall-survival = time from 1Overall-survival = time from 1stst relapse to death from any relapse to death from any causecause

RFI = time from initial diagnosis to 1RFI = time from initial diagnosis to 1stst relapse relapse

Patient CharacteristicsPatient Characteristics

N=43N=43 Males = 27 (63%)Males = 27 (63%) Females = 16 (37%)Females = 16 (37%) median age at primary Dx = 15 y (4.5 – median age at primary Dx = 15 y (4.5 –

31.4)31.4) primary extremity tumors = 38 (88%)primary extremity tumors = 38 (88%) primary axial tumors = 5 (12%)primary axial tumors = 5 (12%) metastases at primary diagnosis = 10 (23%)metastases at primary diagnosis = 10 (23%)

Median time to 1Median time to 1stst relapse < 24 relapse < 24 months after diagnosismonths after diagnosis

median time to 1median time to 1stst relapse = 21.7 months relapse = 21.7 months (4.6 – 135.7) from primary dx(4.6 – 135.7) from primary dx

# achieved CR2 = 26 / 43 (60%)# achieved CR2 = 26 / 43 (60%)

Lungs are the most common sites Lungs are the most common sites of relapseof relapse

Sites of relapseSites of relapse lungs alone = 22lungs alone = 22

unilateral = 13unilateral = 13 bilateral = 9bilateral = 9 multiple nodules = 13multiple nodules = 13 solitary nodules = 9solitary nodules = 9

local = 6local = 6 bone = 14bone = 14 lung + other = 11lung + other = 11 soft tissue (incl. liver) = 3soft tissue (incl. liver) = 3

35% Crude Overall Survival35% Crude Overall Survival

Total alive = 15 / 43 (35%)Total alive = 15 / 43 (35%)** Alive with disease = 4Alive with disease = 4 Alive without disease = 11Alive without disease = 11

Median Follow-Up after R1 = 15.2 months Median Follow-Up after R1 = 15.2 months (0.7-158.3)(0.7-158.3)

Survival at Median Follow-Up after R1 = Survival at Median Follow-Up after R1 = 26 / 43 (60.5%)26 / 43 (60.5%)

*as of July 2004

Overall Survival from 1Overall Survival from 1stst Relapse Relapse

Time (months)

Pro

por

tion

Sur

vivi

ng

Progressive disease is the most Progressive disease is the most common cause of death after 1common cause of death after 1stst relapserelapse

Causes of death: Causes of death: progressive OS = 23progressive OS = 23 sepsis = 2 (1 in CR)sepsis = 2 (1 in CR) ARDS = 2 (1 in CR)ARDS = 2 (1 in CR) 22oo AML/MDS = 1 (in CR) AML/MDS = 1 (in CR)

Survival correlated with RFI > 24 Survival correlated with RFI > 24 months and achievement of CR2months and achievement of CR2

RFI > 24 months = 9/17 RFI > 24 months = 9/17 (53%)(53%)

Achieving CR2 = 15/26 Achieving CR2 = 15/26 (58%)(58%)

Lungs – unilateral = 7/13 Lungs – unilateral = 7/13 (54%)(54%)

Lungs – solitary = 5/9 Lungs – solitary = 5/9 (56%)(56%)

RFI < 24 months = 6/26 RFI < 24 months = 6/26 (23%)(23%)**

Not achieving CR2 = 0/17 Not achieving CR2 = 0/17 (0%)(0%)**

Lungs – bilateral = 2/9 (22%)Lungs – bilateral = 2/9 (22%)

Lungs – multiple = 4/13 (31%)Lungs – multiple = 4/13 (31%)

* p<0 .05

Treatment Strategies for R1Treatment Strategies for R1

Surgery alone = 4Surgery alone = 4 2/4 relapsed after CR22/4 relapsed after CR2 overall survival = 3/4overall survival = 3/4

Chemotherapy alone = 7Chemotherapy alone = 7 overall survival = 0/7overall survival = 0/7

Chemotherapy + Surgery = 32Chemotherapy + Surgery = 32 For those +CR2, 11/22 relapsedFor those +CR2, 11/22 relapsed overall survival = 12/32overall survival = 12/32

Multiple chemotherapeutic Multiple chemotherapeutic strategies were utilized in 1strategies were utilized in 1stst relapserelapse

Ifosfamide / EtoposideIfosfamide / Etoposide Cisplatin / Cisplatin /

DoxorubicinDoxorubicin HD MethotrexateHD Methotrexate HD HD

CyclophosphamideCyclophosphamide IrinotecanIrinotecan Gemcitabine Gemcitabine ++

DocetaxelDocetaxel MitoxantroneMitoxantrone

Cyclophosphamide / Cyclophosphamide / TopotecanTopotecan

CarboplatinCarboplatin 5-Flourouracil5-Flourouracil ThioguanineThioguanine Other agents Other agents

(trimetrexate, ET-743, (trimetrexate, ET-743, STI571, trastuzumab, STI571, trastuzumab, Dx-8951f, Dx-8951f, interferon/VP16, Gm-interferon/VP16, Gm-CSF)CSF)

Chemo + Surg (n=32): Overall Chemo + Surg (n=32): Overall Survival since R1Survival since R1

Chemo + Surg (n=32): Relapse Chemo + Surg (n=32): Relapse Free Survival since R1Free Survival since R1

For Chemo + Surg: regimens +IFOS For Chemo + Surg: regimens +IFOS confer advantage in preventing 2confer advantage in preventing 2ndnd relapserelapse

23 patients received IFOS as part of R1 23 patients received IFOS as part of R1 treatment treatment CR2 = 18CR2 = 18 R2 = 8R2 = 8

9 patients did not receive IFOS as part of 9 patients did not receive IFOS as part of R1 treatmentR1 treatment CR2 = 4CR2 = 4 R2=3R2=3

+IFOS (n=23) vs. -IFOS (n=9) +IFOS (n=23) vs. -IFOS (n=9) regimens: Relapse Free Survival after regimens: Relapse Free Survival after R1R1

=+Ifos

=-Ifos

HD IFOS (n=22) vs. all other chemo HD IFOS (n=22) vs. all other chemo regimens (n=10): Overall Survival after regimens (n=10): Overall Survival after R1R1

=HD Ifos

=other

ConclusionsConclusions

Chemotherapy with curative-intent Chemotherapy with curative-intent surgery can successfully salvage 22/32 of surgery can successfully salvage 22/32 of patients at 1patients at 1stst relapse relapse 9/32 remain 9/32 remain NED.NED.

Chemotherapy regimens containing Chemotherapy regimens containing ifosfamide appear to confer an advantage ifosfamide appear to confer an advantage in preventing a 2in preventing a 2ndnd relapse. relapse.

Paul A. Meyers, MDPaul A. Meyers, MD

Pediatric Sarcoma Pediatric Sarcoma Team Team Leonard H. Wexler, MDLeonard H. Wexler, MD Richard Gorlick, MDRichard Gorlick, MD Pamela R. Merola, MDPamela R. Merola, MD Yatin Vyas, MDYatin Vyas, MD Karen Allison, CPNPKaren Allison, CPNP Jamie Viccola, CPNPJamie Viccola, CPNP Stephanie Vitolano, Stephanie Vitolano,

CPNPCPNP

Surgical TeamSurgical Team Michael P. LaQuaglia, Michael P. LaQuaglia,

MDMD John H. Healey, MDJohn H. Healey, MD

Andrew G. Huvos, MDAndrew G. Huvos, MD

DFS For HD IFOS group: IFOS DFS For HD IFOS group: IFOS naïve (n=19) vs. IFOS exposed naïve (n=19) vs. IFOS exposed (n=3)(n=3)

=IFOS naive

=IFOS exposed

From Hawkins et al, Cancer 2003

Comparison of DFSComparison of DFS

=chemo + surg

=surg

Time (months)

Pro

por

tion

Sur

vivi

ng

From Hawkins et al, Cancer 2003

Comparison of Overall SurvivalComparison of Overall Survival

Time (months)

Pro

por

tion

Sur

vivi

ng

chou aj, merola pr, vyas y, wexler l, gorlick r, laquaglia m, healey j, huvos a, meyers pa

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