Soft Tissue Sarcoma Flashcards
What are the molecular classifications of STS?
1) Kinase mutations
2) Recurrent translocation
3) Gene inactivation
4) Simple genetic alterations
5) Complex cytogenetics
What is an example of kinase mutation and what are genes involved?
KIT, PDGFRA
Example = GIST
What is an example of recurrent translocation and what are genes involved?
- t(11;22) = Ewing’s sarcoma
- t(X;18) = Synovial Sarcoma
- t(2;13); t(1;13) = Alveolar rhabdomyosarcoma
What is an example of gene inactivation and what are genes involved?
Loss of INI1 = Epitheloid sarcoma
What is an example of simple genetic alteration and what are genes involved?
MDM2 = Liposarcoma
What is an example of complex cytogenetics and what are genes involved?
Leiomyosarcoma
Angiosarcoma
Does adjuvant RT improve local control? How about survival benefit?
YES. Adjuvant RT improves local control. But NO SURVIVAL BEEFIT
Evidence comes from Yang et al JCO 1998 NCI-led study, n=90 Operable STS of extremity & Superficial trunk 2 arms: 1) Surgery 2) Surgery + RT (EBRT up to 63Gy)
Any difference btwn pre and post-op RT?
Brian O’sullivan Lancet 2002
No difference in OS and no differences in local/Regional/distant failures
RT Dose:
- pre op = 50 Gy + 16Gy boost if margins +
- post op = 66 Gy
Wound complications:
35% pre-op
17% post-op
Pre-op RT filed is smaller, and a smaller dose required
Post-op gives the advantage of more tissue
Complications:
Pre-op: More early reversible complications like wound infections
Post-op: More ate irreversible complications like fibrosis, stiffness, edema
What is the benefit for meta-analysis on adjuvant chemo?
Done by sarcoma meta-analysis collaboration Lancet 1997
1500 patients, 14 trials
Doxorubicin-based chemo, 45% single agent, 2% Doxo-Ifosfamide
RESULTS:
- LR-free interval = 6%
- Distant RFS = 10%
- Oerall RFS 10%
- OS 4% benefit but p 0.12
What is CYVADIC chemotherapy?
CYclophosphamide
Vincristine
DoxorubicIn
Dacarbazine
Any value in using CYADIC?
Bramwell JCO 1994
PFS and LRFS with improvement
But Met FS and OS not significant
What is the evidence for AI?
Lancet Oncol 2012 Woll et al EORTC 62931
Grade II/III STS - excluded EWS/RMS S/p complete or marginal excision Post-op RT if: - Marginal excisions - previous incomplete surgery - locally recurrent disease
2 arms:
1) AI Q3w
- Doxo (65)
- Ifsofamide (5) with Mensa IV 24hours at D1
- Lenograstim 4 micrograms/kg X 14 days
RESULTS:
No benefit in RFS and OS
What are the palliative 1st line options?
Anthracyclines +/- Ifosfamide
What are the palliative 2nd line options?
Gemcitabine- Docetaxel
Pazopanib
Trabecedin
Dacarbazine
What are the palliative post-2nd line options?
Off labels
Clinical trials
How do we decide single agent vs combination chemotherapy ?
Bramwell Sarcoma 2004 meta-analysis
8 trials, 2200 patents
More chemo = higher response but more toxicity
No OS differences
Trend towards RR
- Objective response 15-20% (Single agent) vs 30% (Combi)
- CR
Was there any evidence between Doxorubicin and Liposomal Doxorubicin?
Judson et al. European journal of cancer
N=94
2 arms:
- Liposomal doxorubicin 50mg2/Q4 weeks
- Doxorubicin (75=90mg/m2)
ORR: 10% vs 9%
TTP; 2.3m. Vs 2.9m
Med OS 11.4m vs 8.8m
Any evidence to re-challenge Ifosfamide?
YES. JCO A. Le Cesne
N=40 patients
28 pre-treated with standard dos Ifosfamide
A) Standard
B) HD Ifosfamide 12g/m2/ Q4 weeks
RESULTS:
Significant toxicities
RR 33%
All but one had prior standard dose Ifosfamide
CONCLUSION: High dose Ifosfamide may circumvent the resistance
How about what is the evidence for Gem-Docetaxel?
Single Centre MSKCC
Study ORR 50%
Metastatic STS
Hensley JCO
Maki Oncol 2007
SARCOMA 002 - Gemcitabine +/- Docetaxel
Met STS, n=120 0-3 prior regimens Improved PFS: 6m vs 3m Improved OS 18m s 11m
RR 16% vs 8%
What is the pivotal Trabectedin study?
JCO 2009
Demetri et al
Includes; - leiomyosarcoma and liposarcoma - 2 arms: >> : Q3w 24 hour >> Arm 4 = Q3Weekly
RESULTS:
Med TTP 3.7m vs 2.3m
RR 5.% arm B 50% vs 45% (3y PFS)
Median OS 13.9m and 11.8m (not sigg)
