Soft Tissue Sarcoma

Question 1

What are the molecular classifications of STS?

Answer 1

1) Kinase mutations
2) Recurrent translocation
3) Gene inactivation
4) Simple genetic alterations
5) Complex cytogenetics

Question 2

What is an example of kinase mutation and what are genes involved?

Answer 2

KIT, PDGFRA

Example = GIST

Question 3

What is an example of recurrent translocation and what are genes involved?

Answer 3

• t(11;22) = Ewing’s sarcoma
• t(X;18) = Synovial Sarcoma
• t(2;13); t(1;13) = Alveolar rhabdomyosarcoma

Question 4

What is an example of gene inactivation and what are genes involved?

Answer 4

Loss of INI1 = Epitheloid sarcoma

Question 5

What is an example of simple genetic alteration and what are genes involved?

Answer 5

MDM2 = Liposarcoma

Question 6

What is an example of complex cytogenetics and what are genes involved?

Answer 6

Leiomyosarcoma

Angiosarcoma

Question 7

Does adjuvant RT improve local control? How about survival benefit?

Answer 7

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)

Question 8

Any difference btwn pre and post-op RT?

Answer 8

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

Question 9

What is the benefit for meta-analysis on adjuvant chemo?

Answer 9

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

Question 10

What is CYVADIC chemotherapy?

Answer 10

CYclophosphamide
Vincristine
DoxorubicIn
Dacarbazine

Question 11

Any value in using CYADIC?

Answer 11

Bramwell JCO 1994
PFS and LRFS with improvement
But Met FS and OS not significant

Question 12

What is the evidence for AI?

Answer 12

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

Question 13

What are the palliative 1st line options?

Answer 13

Anthracyclines +/- Ifosfamide

Question 14

What are the palliative 2nd line options?

Answer 14

Gemcitabine- Docetaxel
Pazopanib
Trabecedin
Dacarbazine

Question 15

What are the palliative post-2nd line options?

Answer 15

Off labels

Clinical trials

Question 16

How do we decide single agent vs combination chemotherapy ?

Answer 16

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

Question 17

Was there any evidence between Doxorubicin and Liposomal Doxorubicin?

Answer 17

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

Question 18

Any evidence to re-challenge Ifosfamide?

Answer 18

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

Question 19

How about what is the evidence for Gem-Docetaxel?

Answer 19

Single Centre MSKCC
Study ORR 50%

Metastatic STS

Hensley JCO
Maki Oncol 2007

Question 20

SARCOMA 002 - Gemcitabine +/- Docetaxel

Answer 20

Met STS, n=120
0-3 prior regimens
Improved PFS:
6m vs 3m
Improved OS 18m s 11m

RR 16% vs 8%

Question 21

What is the pivotal Trabectedin study?

Answer 21

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)