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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

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Disclosures

• None

• No financial relationship with the database described

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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

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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?

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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

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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

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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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Patient Characteristics

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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

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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*

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Pre-op RT vs. Post-op RT

Overall Survival Cause-specific Survival

log-rank, p=0.07 log-rank, p<0.05

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Pre-op RT vs. Post-op RT

LF-free Survival DM-free Survival

log-rank, p<0.05 log-rank, p<0.001

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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

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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%

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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

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Thank You