Role of radiotherapy in sarcomas and especially extremity sarcomas

1. ROLE OF RADIOTHERAPY IN
SOFT TISSUE SARCOMAS
Dr. Ashutosh Mukherji
Senior Consultant and Academic Coordinator,
Department of Radiation Oncology
Yashoda Hospital, Hyderabad, India

2. 2

3. 3

4. What is the Role of Radiation Therapy
in Limb Salvage?
4

5. 5

6.  The treatment of soft-tissue sarcomas of the extremities: prospective
randomized evaluations of (1) limb-sparing surgery plus radiation
therapy compared with amputation and (2) the role of adjuvant
chemotherapy. Rosenberg SA, Tepper J, et al Ann Surg. 1982 Sep;196
(3):305-15.
 The only randomized trial published till date comparing limb sparing
surgery followed by adjuvant radiation therapy versus amputation
showed that there was no difference in local disease control & overall
survival between the two treatment groups.
6

7. 7
Radiotherapy – role in optimising local
control
• Local control rates for combination of
surgery + radiotherapy similar to
amputation without affecting patient
survival (Potter et al; 1986).
• Yang et al, J Clin Oncol, 1998, looked
at high grade extremity lesions: Surgery
vs Surgery + EBRT (63Gy in 1.8Gy),
- increased local control from 70%
to 99%, No difference in OS.
Summary: Post operative radiotherapy is highly
effective in preventing local recurrence.
• Brachytherapy can be used as the sole therapy if target volume
is localized and accessible.
• Interstitial brachytherapy (BT) found to improve local control
rates (LC) in patients with limb-sparing resections of extremity.

8. • Randomized prospective study of the benefit of adjuvant
radiation therapy in the treatment of soft tissue sarcomas of
the extremity. Yang JC, Chang AE, et al J Clin Oncol; 16(1):197-
203 1998.
• This compared the results of limb sparing surgery alone
compared to limb sparing surgery & adjuvant external beam
radiotherapy (EBRT) showed that there was a significant
decrease in the local recurrence rates in the patients receiving
EBRT. This improvement in local control was not only seen
amongst patients with high/ intermediate grade tumors but
also inpatients with low grade tumors.
8

9. Pre-operative versus Post-operative
Radiotherapy?
9

10. PREOPERATIVE RADIATION
• RTOG Intergroup phase II trial with chemo (modified MAID regimen)
concurrent with pre op RT f/d resection in pts with high risk soft tissue
sarcoma (Grade>2, or >8cm in max diameter) followed by 3 cycles of post
op CT with G-CSF.
• 88% of pts completed pre-op CT and 98% completed RT. Delayed wound
healing observed in 26%.
• Estimated 2yr survival was 95%.
Karybill WG, Spiro I, Harris J, et al: RTOG 95-14; a phase two study of NACT and RT in high risk, high grade, soft
tissue sarcomas of the extremity and the body wall : a preliminary report. PROC ASCO.2001;20:34a

11. OVERVIEW OF PREOP RT
First Author Radiation
Dose (GY)
Study Design No. of Patients Local failure %
Suit 50–56 Retrospective 89 17
Barkley 50 Retrospective 110 10
Brant 50.4 Retrospective 58 9
O'Sullivan 50 RCT 94 7

12. • Preoperative versus postoperative radiotherapy in soft tissue sarcoma of the
limbs: a randomised trial. - O’Sullivan B et al Lancet. 2002 Jun 29;359
(9325):2235-41.
• The only randomized trial published till date comparing pre-operative
versus post-operative radiotherapy showed that post-operative wound
complications (120 days post-op) were significantly higher in the pre-
operative RT group. The overall survival was marginally superior in the
patients receiving pre-operative radiotherapy arm.
• Preoperative vs. postoperative radiotherapy in the treatment of soft tissue
sarcomas: a matter of presentation - Pollack A et al. Improvement in local
control with pre-op EBRT was only in patients with gross disease while the
benefit of postop EBRT was significant in the patients presenting with
unknown margins after gross total resection.
• Pre-operative radiotherapy is beneficial for patients with gross disease/
primary disease while PORT beneficial for patients with unknown surgical
margins after gross total resection.
12

13. 13

14. 14

15. 15

16. Five year actuarial local control for primary soft
tissue sarcoma according to size and RT sequencing
MGH experience
POST OP RT POST OP RT PRE OP RT PRE OP RT
SIZE (mm) Pts, n % Local
Control
Patients, n % Local
control
25 20 100 11 80
25-49 45 95 16 100
50-100 64 83 63 93
101-150 12 91 34 100
150-200 6 50 25 79
200 3 67 11 100
TOTAL 150 87 160 92

17. POST OPERATIVE RADIATION
• MDAH – 300 pts with STS of the extremities, H&N and
retroperitoneum were treated with conservative excision f/b RT
to a total dose of 60-75Gy.
• Local recurrence rates were 20% for extremity, 38% for
abdominal and 23% for H&N sarcomas. 5yr DFS was 61% for all
sites.
• 1/3RD of the extremity failures occurred beyond margins of the
irradiated field. The local control did not change with 10Gy dose
reduction in the later period.
Lindberg RD, Martin RG, Romsdhal MM, et al: Conservative surgery and postoperative RT in 300
adults with soft tissue sarcomas. Cancer. 1981;47:2391.

18.  UCSF : 29 pts with extremity sarcomas were treated with
conservative surgery and post op RT. The majority of the
cases had grade III or larger than 5 cm tumors. The RT dose
Ranged from 50-75Gy. 82% of pts received more than 55Gy.
 The local control rate with surgery + RT was 90%, with a five
year relapse free survival of 68%. Local recurrence rate was
14% for pts receiving post op RT vs 79% was those receiving
Surgery alone.
 These results were superior to excisional surgery alone and
comparable to radical surgery on a stage by stage basis.
Leibel SA, Trenberg RF, Wara WM, et al: Soft tissue sarcomas of the extremities; survival and
patterns of failure with conservative surgery and post op RT compared to surgery alone.
Cancer.1982;50:1076

19. First Author
RT Dose
(GY) Study Design
No. of
Patients
Local
Failure (%) Subset
Karakousis 45–60 Retrospective 53 14
Suit 60–68 Retrospective 131 12
Yang 45 + 18 RCT 91 0 (high-grade)
50 5 (low-grade)
O'Sullivan RCT 96 7
Lindberg 60-75 Retrospective 300 22

20. Indications for Adjuvant RT
• All High Grade STS.
• Low-Int Grade STS with close or positive margins.
• Tumour recurrence
• Tumor size of >5 cm,
• Lesions deep to or invading the superficial fascia,
and younger than 50 years
BRACHYTHERAPY –
ABS recommendations for use of brachytherapy in
different situations
• When the tumour is completely resected (Gr2 –
Gr3): surgery followed by brachytherapy alone;
• When the CTV cannot be adequately implanted,
and the surgical margins are positive:
• Surgery followed by brachytherapy and EBRT.
• Other situations, different kinds of brachytherapy
may be indicated
20
Preop RT indicated if:
• If tumour adjacent to or
involving critical
• structures.
• Likely difficult resection.
• Tumour initially
inoperable at diagnosis

21. COMBINED CONSERVATIVE SURGERY AND
RADIATION THERAPY
Treatment Advantages Disadvantages
Preoperative
radiation
1. Smaller treatment volume
2. Decreases risk of surgical implant or
dissemination
3. Smaller surgery
4. Increases tumor resectibility
1. Delay in surgery
2. Delay in wound healing
3. Diagnosis based on small tissue
specimen
4. Need to relay on good radiographic
images and physical examination to
asses the tumor extent
Postoperative
radiation
1. Immediate surgery
2. Tumor extent assessed directly by surgery
3. Larger specimen for pathological diagnosis
4. No radiation induced delay in wound healing
1. Larger treatment volume
2. Delay in radiation
Brachytherapy/
IORT
1. Radiation applied directly to tumor bed
2. Minimizes radiation damage to surrounding
tissue
3. No delay in radiation to allow for tumor
repopulation and hypoxia
4. Shortens treatment time with possible cost
reduction
1. Needs local expertise in IORT or
brachytherapy
2. Requires close cooperation between
surgeon and oncologist
3. Treatment volume is limited to direct
tumor bed
4. Radiation exposure to hospital staff

22. Can we avoid Radiation Therapy for
High Grade STS with Wide Surgical
Margins?
22

23. • Long-term results of prospective trial of surgery alone with selective use of
radiation for patients with T1 extremity and trunk soft tissue sarcomas.
Pisters PW et al. Ann Surg. 2007 Oct;246(4):675-81; discussion 681-2. This
study from MD Anderson Cancer Centre reported local recurrence rates of
8% & 11% at 5 & 10 years for patients with T1a lesions having undergone R0
resection and no further adjuvant therapy.
• Improved survival with radiation therapy in high-grade soft tissue Sarcomas
of the extremities: a SEER analysis. Matthew Koshy et al. Int. J. Radiation
Oncology Biol. Phys., Vol. 77, No. 1, pp. 203–209, 2010. SEER data suggested
that adjuvant RT could possibly be avoided in patients with T1 (<5cm) who
have undergone WLE with negative surgical margins. The results need to be
interpreted in the correct perspective as this being a nonrandomized study
and patients with poor prognostic features went on to receive adjuvant
radiotherapy.
23

24. • Surgery alone is adequate treatment for early stage soft tissue sarcoma of
the extremity. Al-Refaie WB et al. Br J Surg. 2010 May;97(5):707-13.
• Association of local recurrence with subsequent survival in extremity soft
tissue sarcoma.- Lewis JJ et al. J Clin Oncol. 1997 Feb;15(2):646-52.
In the absence of randomized trial addressing the issue of adjuvant
radiotherapy for T1 high grade STS; it would be advisable to treat such patients
with radical interstitial brachytherapy that would be ideal for patients with
such small lesions.
24

25. What is the benefit of Radiation
Therapy for Low Grade STS?
25

26. • Randomized prospective study of the benefit of adjuvant radiation therapy in
the treatment of soft tissue sarcomas of the extremity. Yang JC et al ; J Clin
Oncol; 16(1):197-203 1998. The authors reported 50 patients with low-grade
lesions (24 randomized to resection alone and 26 to resection and
postoperative XRT), there was a lower probability of local recurrence (p
=0.016) in patients receiving adjuvant radiotherapy, although without a
difference in overall survival.
This is the only RCT. Thus Adjuvant radiotherapy can be avoided only in very
select group of patients in the absence of any of the adverse prognostic factors
like deep seated tumor, >5cm, & close or positive surgical margins
26

27. Impact of Interval between Surgery &
Radiation Therapy?
27

28. • Interval between surgery and radiotherapy: effect on local control of soft
tissue sarcoma. Ballo MT, et al. Int J Radiat Oncol Biol Phys. 2004 Apr 1;58
(5):1461-7.
• The records of 799 patients post PORT for soft tissue sarcoma between
1960 and 2000 were retrospectively reviewed. Univariate and multivariate
analyses were used to evaluate the potential impact of the timing of
postoperative RT on the rate of local control (LC).
• A delay between surgery and the start of RT of >30 days was associated
with a decreased 10-year LC rate, but this association was not statistically
significant (76% vs. 83%, p = 0.07). The potential association between RT
delay and inferior LC attributed to an imbalance in the distribution of other
prognostic factors.
• The authors concluded that the interval between surgery and RT did not
significantly impact the 10-year LC rate and that an RT delay should not be
viewed as an independent adverse factor for LC. Treatment intensification
may not be necessary for patients with treatment delay.
28

29. Wither Safe Margins?
29

30. 30
Usual extent of
surgical excision

31. • 2217 patients with nonmetastatic extremity and truncal STS treated with
surgical resection and multidisciplinary consideration of perioperative
radiotherapy were retrospectively reviewed.
• Margins were coded by residual tumor (R) classification (in which
microscopic tumor at inked margin defines R1), the R+1mm classification
(in which microscopic tumor within 1 mm of ink defines R1)
• Toronto Margin Context Classification (TMCC; in which positive margins
are separated into planned close but positive at critical structures, positive
after whoops re-excision, and inadvertent positive margins).
31

32. • The AJCC manual describes an R0 margin as free of malignancy, an
R1 margin is defined as microscopic tumor cells present at the inked
border of the specimen, and R2 refers to a grossly positive margin.
• Several studies of surgical margins in extremity STS have used this
definition and found it prognostic for LR.
• Other authors have defined a surgical margin of < 1mm from tumor
as microscopically positive; this system has likewise been reported
as prognostic for LR.
• Current guidelines recommend complete resection of STS with a
negative surgical margin, without a specific recommendation for
the width of that margin or a standard definition of a negative
margin
32

33. • By R classification, LR rates at 10-year follow-up were 8%, 21%, and 44% in
R0, R1, and R2, respectively.
• R+1mm classification resulted in increased R1 margins (726 v 278, P<.001),
but led to decreased LR for R1 margins without changing R0 LR; for R0, the
10-year LR rate was 8% (range, 7%to 10%); for R1, the 10-year LR rate was
12% (10% to 15%) .
• The TMCC also showed various LR rates among its tiers (P<.001). LR rates
for positive margins on critical structures were not different from R0 at 10
years (11% v 8%, P = .18), whereas inadvertent positive margins had high
LR (5-year, 28% [95% CI, 19% to 37%]; 10-year, 35% [95% CI, 25% to 46%];
P < .001).
33

34. 34

35. 35

36. 36

37. 37

38. DOSE VOLUME GUIDELINES FOR ADJUVANT RT
FOR EXTREMITY SOFT TISSUE SARCOMA
Mode of RT Treatment
phase
Volumetric coverage Dose
Preoperative EBRT Phase 1
Phase 2
GTV + 4cm CTV margin
Original GTV + 2cm CTV margin
50Gy/25#/5wks
If required
Postoperative
EBRT
Phase 1
Phase 2
Limits of surgical dissection
including scars and drain sites
plus 4cm CTV margin
High risk target volume(original
GTV and surgical scar) plus 1cm
CTV margin
50Gy/25#/5wks
16Gy/8#/1.3wks
Brachytherapy Course Surgical bed plus 2cm 45Gy in 4-6days

39. • Circumferential irradiation of extremity results in severe fibrosis
with pain, edema and loss of function – try to spare as much
normal tissue compartments as possible or at-least 1cm strip of
normal tissue.
• Portion of circumference of uninvolved bone should be spared to
prevent fracture
• Bolus should be kept over the surgical scar
• If the scar crosses a joint, part of joint should be blocked out unless
the joint was violated surgically
• Gonadal shielding
• Long fields – gapped, match line to be moved weekly
• Wedge filters and compensators

40. Dosages
 NCI guidelines – post op dose 63Gy at 1.8Gy fractions, 70-75Gy for gross
residual disease
 NCCN guidelines 2008
Post op RT
Positive margins- 50Gy/25#/5wks EBRT
+ 20Gy BRT boost
Negative margins - 45Gy BRT
OR
IORT f/b 50Gy/25# /5wks EBRT
OR
Microscopically positive margins- 50Gy/25#/5wks EBRT
+16 – 20Gy boost
Macroscopically positive margins - 50Gy/25#5wks EBRT
+ 20-24Gy boost
Negative margins- 50Gy/25# EBRT
+10-16Gy boost

41. Can Radical Interstitial Brachytherapy
obviate the need for External Beam
Radiation Therapy?
41

42. 42

43. • With a median follow-up time of 76 months, the 5-year
actuarial local control rates were 82% and 69% in the BRT and
no BRT groups (P = .04), respectively.
• Patients with high-grade lesions had local control rates of 89%
(BRT) and 66% (no BRT) (P = .0025).
• BRT had no impact on local control in patients with low-grade
lesions (P = .49).
• The 5-year freedom-from-distant-recurrence rates were 83%
and 76% in the BRT and no BRT groups (P = .60), respectively.
43

44. 44

45. Perioperative Interstitial Brachytherapy for Soft Tissue Sarcomas:
Prognostic Factors and Long-Term Results of 155 Patients
Annals of Surgical Oncology; February 2007, Volume 14, Issue 2,
pp 560–567, Laskar et al
• 60% had lesions involving the lower extremities. Treatment included
wide local excision of primary tumor with BRT with or without
external beam radiotherapy (EBRT).
• median follow-up 45 months, the local control (LC), disease-free
survival (DFS), and overall survival (OS) was 71%, 57%, and 73%,
respectively.
• DFS was superior for superficial tumors compared with that for deep
tumors (96% vs. 54%, P =0.02). Tumor size less than 5 cm had
superior OS (88% vs. 63%, P =0.05).
• Cumulative radiotherapy dose greater than 60 Gy had a significant
positive impact on LC (P = 0.003), DFS (P =0.003), and OS (P =0.048).
45

46. RESULTS ADJUVANT HDR
BRACHYTHERAPY IN SOFT TISSUE
SARCOMAS OF EXTREMITIES
46
Author Brachy used Sample size Local control% Complications %
Alekhteyar LDR-HDR 18 90 38
Chuba HDR 32 82 48
Crownover HDR 10 100 0
Donath HDR 19 70 16
Koizumi HDR 16 50 6
Pellizzon HDR 25 84 24
Yoshida HDR 13 72 8

47. RESULTS ADJUVANT LDR
BRACHYTHERAPY IN SOFT TISSUE
SARCOMAS OF EXTREMITIES
47
Author Brachy used Sample size Local control % Complications %
Chaudhary LDR 118 96 10
Cionini LDR 33 91 6
Gemer LDR 25 80 36
O’ Connor LDR 68 91 22
Schray LDR 63 96 10
Thomas LDR 57 89 28
Rosenblatt LDR 11 100 15

48. American Brachytherapy Society (ABS)
consensus statement for sarcoma brachytherapy
• Adjuvant external beam radiation therapy (EBRT) or brachytherapy
(BT) can enhance local control (LC) in patients undergoing limb-
sparing sarcoma resections in the extremity and is supported by
Level 1 evidence.
• No controlled studies comparing EBRT with BT.
• Limitations for BT are large target volumes, restrictions in catheter
placement because of bone or visceral organs, anatomic sites
where good catheter geometry may be difficult to achieve (i.e.,
around the shoulder), and risk of radiation injury to nerves.
• There is no consensus on whether BT should be combined with
EBRT in the setting of positive margins or whether one modality is
sufficient.
48

49. • Results from Memorial Sloan Kettering (MSKCC): improved with
addition of interstitial brachytherapy to RT in adjuvant setting
with positive margins and recurrent disease.
• MSKCC group noticed that shoulder location was an independent
prognostic factor for poor local control with interstitial
brachytherapy.
• BT in combination with external beam is recommended for cases
with recurrent disease who have not been previously irradiated.
49

50. What I would like from my surgeon
• Place metallic clips at boundaries of
resection
• Skin exit point of drain to be near the
incision
• Bury the neurovascular bundle if
exposed and mark the site with a clip
• Please give me clear radial margins; RT
boost does not improve results, better
to re-excise for clear margins
50

51. 51

52. TARGET VOLUME
• Target volume: defined from preoperative imaging and /or intra
operative evaluation.
• The GTV is based on imaging (MRI) and the pre-operative
description,
• CTV is considered to be the ex-GTV plus a 2 - 3 cm margin for BT.
The radio-opaque markers or clips placed at the time of surgery
help the physician contour the CTV.
5 - 10 cm margin around the tumour bed is used for external beam
therapy. However, margins are now considered to be based more on
anatomical muscular compartments than on cm margins.
52

53. 53
Exposed Neuro-vascular
bundle can be “buried”
under a muscular
pedicle
The bed or the
target volume
is re-aligned
anatomically by
stay sutures

54. 54
Intraoperative placement of brachytherapy catheters
demonstrating both (a) parallel and (b) perpendicular
orientation of the catheters in relation to the wound.

55. 55
Implantation of the
metallic needles
Replacement of the
needles by parallel
plastic tubes

56. • The positioning of the plastic tubes is adapted to the dimensions
of the CTV. Parallel and equidistant plastic tubes are spaced 10 to
20 mm, according to the depth of the tissue to be treated.
• To achieve good parallelism and equidistance between the plastic
tubes, they can be partially fixed by surgical sutures either inside
the tumour bed or at skin level (at the entrance and exit points).
• CT simulation is the current standard for BT dosimetry of
sarcomas. It allows for 3D dosimetry of the implant.
• Presentation of axial isodose curves, dose volume histogram
(DVH) data, and virtual images facilitates understanding of the
target doses and permits placement of dose constraints.
56

57. 57
Closing of the surgical bed;
pre-perforated catheters
maintain the equidistance
of the plastic tubes
Surgical scar and
plastic tubes

58. • The quality of the implant can be measured in terms of
– D90 (dose to 90% of the CTV),
– V100 (percent of the CTV that receives the 100% isodose),
– V150 (percent of the CTV that receives the 150% isodose).
• attempt should be made to limit the dose to the surgical incision
to less than 100% isodose unless it is considered at high risk for
tumor involvement.
• The dose to the skin ideally should be no more than two-thirds of
the prescribed dose.
• In addition, source loading should be no closer than 0.5 cm from
the skin surface to minimize skin toxicity.
58

59. 59
3D CT-based dosimetry of an implant in (a) coronal and (b)
axial planes. The 150-50% isodoses are demonstrated. (b)
Surgical clips help to delineate the clinical target volume

60. 60
Dose covering 50%
isodose line
Dose covering 90%
isodose / prescribed dose

61. 61

62. 62

63. 63
Treated sites
(over the anterior shoulder)

64. 64
Expected CTV marked out with wire before
CT scan

65. 65
Thermoplastic frame fixed to
area; dental wax layered over to
prepare mould of required
thickness; catheters marked and
fixed into the mould and again
positioned on patient to check
feasibility of catheter placement
and lesion coverage.

66. 66

67. 3D VIEW WITH MOULD IN PLACE
67

68. Brachytherapy vs IMRT?
68

69. 69
134 adult patients with high-grade primary
non-metastatic STS of the extremity were
treated at this institution with limb-sparing
surgery and adjuvant radiotherapy (RT).
Median follow-up was 46 months for IMRT
and 47 months for BRT. 5-year local control
was 92% (95% confidence interval [CI], 85-
100) for IMRT versus 81% (95% CI, 71-90)
for BRT, P ¼ 0.04. On multivariate analysis,
IMRT was the only predictor of improved
local control, P ¼ 0.04.

70. • Impact of intensity-modulated radiation therapy on local control in primary
soft-tissue sarcoma of the extremity. Alektiar KM et al. J Clin Oncol. 2008 Jul
10;26(20):3440-4.
• Intensity modulated radiation therapy for retroperitoneal sarcoma: a case for
dose escalation and organ at risk toxicity reduction. Koshy M, Landry JC, et al.
Sarcoma. 2003;7(3-4):137-48.
IMRT in STS of the extremity provides excellent local control in a group of
patients with high risk features. This suggests that the precision with which
IMRT dose is distributed has a beneficiary effect in sparing normal tissue and
improving local control.
70

71. Conclusions
 Historically deemed radio-resistant.
 IMRT should be considered to improve outcome
 If resections with microscopically or grossly positive
margins is expected, surgical clips should be left in place
to identify high risk areas for recurrence (retro
peritoneal, intra-abdominal sarcomas)
 Total dose of RT is determined by normal tissue
tolerance
 RT alone is reserved for pts with unresectable lesions
due to anatomic location, medical inoperability or
refusal to undergo surgery

72. Conclusions
• Adjuvant brachytherapy improves local control after complete
resection of soft tissue sarcomas especially in high-grade
tumours. IMRT in recent years can replicate results.
• But brachy does not significantly reduce distant metastasis or
improve disease-specific survival.
• Surface mould brachytherapy useful alternative to interstitial
brachytherapy. Important where target volume is extensive /
underlying critical structures present or catheter placement
difficult.
Areas like nose, scalp, peri-orbital regions, shoulder or knees
areas where surface mould brachytherapy can be successfully
applied

73. THANK YOU