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HCI Sarcoma Services
Sequential Dependency of Radiotherapy for Soft-Tissue Sarcoma
S Sampath TE Schultheiss YJ HitchcockRL Randall DC Shrieve JYC Wong
CTOS, Miami Beach, FLNovember 7, 2009
HCI Sarcoma Services
Introduction• The sequencing of RT with surgery in soft-
tissue sarcoma remains controversial• O’Sullivan et al (Lancet 2002): first and
only randomized trial comparing pre-op vs. post-op RT– Primary endpoint: Rate of wound
complications at 4 months increased with pre-op RT
– No difference in sarcoma-specific survival but slight improvement in OS
HCI Sarcoma Services
Study Questions
• Is there clinical justification using pre-op over post-op RT on the basis of a survival endpoint?
• Besides stage and grade, are there other robust prognostic factors for survival?
• Are there specific subgroups who may benefit from a pre-op RT approach?
HCI Sarcoma Services
Methods• National Oncology Database
– IMPAC® Medical Systems (Sunnyvale, CA)– Data entry by certified registrars– Meets regulatory reporting requirements from ACoS,
NAACCR, NPCR, AJCC, SEER, IACR – Aggregate of merged tumor registries from over 150
institutions across the United States– Superior to SEER/Medicare as it contains local and
distant failure information, RT dosing, and chemotherapy– 1984-2005
HCI Sarcoma Services
Connective soft-tissues of the head/neck/face, extremity,
thorax, abdomen, pelvis, peritoneum, retroperitoneum
Age< 18 yearsEwing’s sarcoma
RhabdomyosarcomaDesmoid
DFSPRecurrent disease at
database entry
Unknown variables:
Stage, grade, dates of last
contact, status
3,110 Patients
HCI Sarcoma Services
Cox proportional HRs, K-M Log Rank AnalysisSPSS® 12.0 software (SPSS Inc., Chicago, IL).
• clinical stage• grade• histology • site• size• cause of death • race• gender• margin status • types of failures• dates of failures• surgery• RT sequence• chemotherapy
• Surgery – local tumor removal
NOS – simple excision– wide limb-sparing
resection– amputation– surgery NOS
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Results• Multivariate analysis for OS for the 3,110 patients
showed RT sequence to be a significant variable in model– pre-op RT associated with improved OS compared to
post-op RT (HR 0.76, 95% CI 0.6-0.95, p<0.05)
• Remainder of study consisted of 821 patients who received surgery and either pre-op or post-op RT
• Median follow-up 63 months (0-19 years)• Median RT doses: Pre-op 50.4 Gy, Post-op 60 Gy• Prognostic factors balanced
HCI Sarcoma Services
Results
• Predictors for Overall Survival (p<0.05):
– Age
– Tumor site
– Histology
– RT sequence
– Tumor size
– Stage
• Predictors for Cause-specific Survival (p<0.05):– Age– Histology– RT sequence– Grade– Tumor size– Stage
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Pre-op vs. Post-op RT
95% CI
Endpoint p-value HR lower upper
Overall Survival (n=821)
<0.05 0.73 0.57 0.93
Cause-specific Survival (n=821)
<0.05 0.64 0.47 0.89
Local-failure free Survival (n=709)
<0.05 0.49 0.28 0.88
Distant Metastases-free Survival (n=707)
<0.001 0.37 0.23 0.58
*Post-op RT as comparator variableAbbreviations: RT, radiotherapy; HR, hazard ratio; CI, confidence interval.
Multivariate Analyses*
HCI Sarcoma Services
Pre-op RT vs. Post-op RT
Overall Survival Cause-specific Survival
log-rank, p=0.07 log-rank, p<0.05
HCI Sarcoma Services
Pre-op RT vs. Post-op RT
LF-free Survival DM-free Survival
log-rank, p<0.05 log-rank, p<0.001
HCI Sarcoma Services
Subgroup Analysis - CSS
Synovial Sarcoma Leiomyosarcoma
log rank, p<0.001log rank, p<0.05
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Pre-op vs. Post-op RT StudiesAuthor N Conclusion
Cheng et al (JSO, 1996)
112 No difference in LC
O’ Sullivan et al (Lancet 2002)
190 No difference in CSS
Zagars et al (IJROBP 2003)
517 No difference in CSS
RT sequence not a significant prognostic factor on MVA
Kuklo et al (AJO 2005) 117 No diff. in LC
HCI Sarcoma Services
Synovial Sarcoma & Sequential Dependency
• Guadagnolo et al: IROBP 2007– 150 patients with non-metastatic SS– Pre-op RT led to an increased risk of
distant failures versus post-op RT (50% vs. 40%) but not significant
– No difference in LF or OS.
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Why did Pre-op RT do better?• Hypothesis:
– Post-operative hypoxia may increase development of distant metastases(P=0.01)
– Brizel et al, Cancer Res 1996
P=0.01 pO2
>10 mm Hg
pO2
<10mm Hg
18mo. DFS 70% 35%
HCI Sarcoma Services
Criticism:“If nothing bad is ever said, then nothing good will ever get done”
• Retrospective outcomes study: – Unable to account for:
• performance status • Institutional bias of larger volume sarcoma
centers• Not always clear if grading was a 3 vs. 4 tier
– Under-reporting of chemotherapy (17%)– Heterogeneity of post-treatment follow-up
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Conclusions
• Hypothesis-generating study shows that pre-op RT is associated with improved sarcoma-specific survival compared to post-op RT– Via improved local controldecreased distant
metastases– LMS, SS may be particularly advantaged
• Additional comparative or randomized studies are necessary