PREOPERATIVE HYPOFRACTIONED RADIOTHERAPY IN LOCALIZED

EXTREMITY/TRUNK WALLSOFT TISSUE SARCOMAS

EARLY STUDY RESULTS

Hanna Kosela; Milena Kolodziejczyk; Tadeusz Morysinski; Wirginiusz Dziewirski; Marcin Zdzienicki; Piotr Rutkowski

Department of Soft Tissue/Bone Sarcoma and Melanoma, Department of Radiotherapy

Maria Sklodowska-Curie Memorial Cancer Center and Institute of OncologyWarsaw, Poland

Background

Primary treatment of majority of localized soft tissue sarcoma is surgical resection of the tumor with adequate margins combined with radiotherapy

Using radiotherapy in the local setting increases local control of the disease (with suggested survival benefit for patients with high grade tumors*)

*Koshy M, et al. . Improved survival with radiation therapy in high-grade soft tissue sarcomas of the extremities: a SEER analysis. Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):203-9

Background – preoperative radiotherapy vs postoperative setting

No differences in local recurrence rate, regional and distant failure rates*;*O'Sullivan B, et al. . Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial.2002 Jun 29;359(9325):2235-41.

Benefits Drawbacks

• Lower doses and smaller treatment field size;

• Possible improvement in tumor resectability;

• Smaller incidence in long term radiation- related complications;

Increased risk of wound complications;

Background

Can we shorten the overall treatment time by using hypofractionated radiotherapy and immediate surgery in STS as in rectal carcinoma?

Potential benefits

• Lower risk of tumor clonogens repopulation

• Convenience

• Lower cost

Radiobiological rationale: low α/β ratio: -0,5-5 Gy*

*Gunderson LL, Tepper JE. Clinical Radiation Oncology. London, UK: ChurchillLivingstone; 2007

*

AIM OF THIS PILOT STUDY

Incidence of late complicatons and local recurrences compared to those observed after conventionally fractionated preoperative radiotherapy.

Overall survival;

Patients and methodsIn the years 2006-2010, 262 patients

received 5x5 Gy according to uniform internal preoperative protocol and underwent tumor resection within a consecutive week.

In our analysis we included only

patients with diagnosis of localized, resectable soft tissue sarcoma of the extremities or trunk wall (confirmed pathologically): primary or recurrent; deep seated and/or intermediate/high grade

Patients and methods

• 225 patients• 122 (54%) women, 103 (46%) men• Median age 54 years (range 18-82) • Median follow up 34 months (range 1-80)• Bioethical committee approval

Patients and methods

140 patients (62.2%)- primary tumors• 75 patients (33%) – clinical local recurrence after

previous surgery in another center• 10 patients (4.4%)- after non-radical surgery in

another center, but without clinical recurrence (scar)

56 (24.9%) patients received preoperative chemotherapy

75% of these patients had high grade tumors (G3)

Patients and methods

67.50%

14.70%

17.80%

Tumor localization

Lower limb

Trunk wall

Upper limb

Patients and methods

Synovial sarcoma

Patients and methods

* 16 patients had also postoperative radiotherapy

Tumor size Median size 9cm (range 0,5-41cm)45%>10cm

Tumor grade 29- G1

54-G2

136- G3 (60%)

6- unknown

Final resection margin 176- R0 (78%)

41- R1*

2-R2

Results

• 51 (22.6%) patients were dead at the time of analysis

• 93 (41.3%) recurrences of the disease• 46 - local recurrence (20% local recurrence =

80% local control rate) - in 10 patients after local recurrence amputation was performed

• 78 (34.7%)- distant metastases• 31 (13.8%) patients had local and distant

recurrence of the disease

Overall survival (median - not reached)

0 10 20 30 40 50 60

T ime (months)

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Survival probability

65%

~70%

L o ca l re cu rre n ce -fre e su rvi va l (m e d ia n - n o t re a ch e d )

0 1 2 2 4 3 6 4 8 6 0

T im e (m o n th s)

0 ,0 00 ,0 50 ,1 00 ,1 50 ,2 00 ,2 50 ,3 00 ,3 50 ,4 00 ,4 50 ,5 00 ,5 50 ,6 00 ,6 50 ,7 00 ,7 50 ,8 00 ,8 50 ,9 00 ,9 51 ,0 01 ,0 5

Pro

ba

bility o

f surviva

l

7 3 %

~80%

Factors influencing survival (univariate analysis)

OS:- Tumor size (p = 0.05)- Tumor grade (p = 0.0002)

LRFS:- Tumor grade (p = 0.007)

O v era ll surv iv a l according to tum or grade

0 1 2 2 4 3 6 4 8 6 0

T im e (m o n th s)

0 ,0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Su

rvival p

rob

ab

ility

G 1 +G 2 G 3

p =0 .0 0 0 2

Loca l recurrence-free surv iv a l according to tum or grade

0 1 2 2 4 3 6 4 8 6 0

T im e (m o n th s)

0 ,0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Su

rvival p

rob

ab

ility

G 1 +G 2 G 3

p =0 .0 0 7

O v era ll surv iv a l according to tum or s ize

0 1 2 2 4 3 6 4 8 6 0

T im e (m o n th s)

0 ,0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Su

rvival p

rob

ab

ility

<5 cm 5 -1 0 cm >1 0 cm

p=0.05

Loca l recurrence free surv iv a l according to tum or s ize

0 1 2 2 4 3 6 4 8 6 0

T im e (m o n th s)

0 ,0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Su

rvival p

rob

ab

ility

<5 cm 5 -1 0 >1 0 cm

p =0 .9

Ov erall s urv iv al ac c ording to tumor s tatus

0 12 24 36 48 60

Time (months )

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Survival probability

Pr imary Sc ar af ter non-radic al ex c is ion Clin ic al rec urrenc e

p=0.9

Loc al rec urrenc e-f ree s urv iv al ac c ording to tumor s tatus

0 12 24 36 48 60

Time (months )

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Survival probability

Pr imary Sc ar af ter non-radic al ex c is ion Clin ic al rec urrenc e

p=0.8

`~80%

~~60%

Loca l recurrence-free surv iv a l according to m argins of resec tion

0 1 2 2 4 3 6 4 8 6 0

T im e ( m o n th s)

0 ,0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Su

rvival p

rob

ab

ility

R0 R1

p =0 .0 9

~75%

~~57%

O v era ll surv iv a l according to prim ary tum or s ite

0 1 2 2 4 3 6 4 8 6 0

T im e (m o n th s)

0 ,0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Su

rvival p

rob

ab

ility

Up p e r l im b T ru n k wa l l L o we r l im b

p =0 .1 4

Loca l recurrence free surv iv a l according to tum or s ite

0 1 2 2 4 3 6 4 8 6 0

T im e (m o n th s)

0 ,0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Su

rvival p

rob

ab

ility

p =0 .4 5

Up p e r l im b T ru n k L o we r l im b

O v era ll surv iv a l according to periopera tiv e chem otherapy

0 1 2 2 4 3 6 4 8 6 0

T im e (m o n th s)

0 ,0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1 ,0

Su

rvival p

rob

ab

ility

W i th p re o p ch e m o (n e o a d ju va n t) W i th o u t p re o p ch e m o

p =0 .1 2

Complications of the treatment

97 patients (43%) had postoperative wound complications including 9 patients (4%) who required an additional surgical procedure

33.6% of patients with complications received preoperative chemotherapy

87 patients with wound complications (89.6%) had tumor localized on the lower limb

Early local complications

• 38 (16.9%) patients had prolonged healing of the wound (>1 month)

• 28 (12.4%) patients had wound dehiscence• 9 (4%) patients required prolonged punctures of

the collecting lymph fluid• 6 (2.7%) patients had an increased acute skin

toxicity

Late complications

• 2 (0.8%) patients severe fibrosis leading to contracture of the limb

• 24 (10.7%) patients prolonged edema of the operated limb

• 6 (2.7%) patients - fracture of the treated limb (median time from treatment to fracture 18 months)

Discussion

Discussion

Conclusions

• Local control rates an overall survival similar to those seen in patients treated with preoperative radiotherapy conventionally fractionated;

• Our series comprises majority of high risk patients with large high grade tumors;

• Wound complication - quite high rate of early complications but low percentage of severe complications;

• Late complications - similar to those seen in patients treated with preoperative radiotherapy conventionally fractionated

Clinical trial?

„Short-course” preoperative radiotherapy vs

conventional radiotherapy

• Cancer Center – Institute; Warsaw: K. Wiater, S. Falkowski, A. Klimczak, T. Świtaj, K. Ptaszyński,U. Grzesiakowska, E. Bylina, A, Głuszcz,…

• Our patients and their families

ACKNOWLEDGEMENTS

Thank you for your attention!

Cancer Center, Warsaw, Poland