Late treatmentrelated complications in 214 patients with extremity soft-tissue sarcoma treated by surgery and postoperative radiation therapy

Authors: Lorenzo Livi, M.D. Riccardo Santoni, M.D., Fabiola Paiar, M.D., Paolo Bastiani, M.D., Giovanni Beltrami, M.D., Patrizio Caldora, M.D., Rodolfo Capanna, M.D., Pietro De Biase, M.D., Beatrice Detti, M.D., Simona Fondelli, M.D., Elisa Meldolesi, M.D., Maurizio Pertici, M.D., Caterina Polli, M.D., Gabriele Simontacchi, M.D., Gianpaolo Biti, M.D.
Source: The American Journal of Surgery 191 (2006): 230–234
Affiliation: Department of Radiation Oncology, University of Florence, Florence, Italy

Background

• In the treatment of soft tissue sarcoma (STS), limb sparing surgery is considered an acceptable alternative to amputation, but post-operative radiation is required for optimal local control.
• Risk factors for late complications, such as bone fracture, following wide local excision and post-operative radiation for STS are not well characterized.

Methods

• Design: Retrospective, single institution analysis
• Patients: 214 patients (pts) with extremity soft tissue sarcoma treated with radical surgery and post-operative radiation therapy
• Treatment:
  • 94% had R0 resections; 6% had R1 resections
  • Pts were treated as follows:
    • 27% received external beam radiotherapy (EBRT) alone, with median dose of 66 Gy
    • 73% underwent brachytherapy + EBRT, with median dose of 75 Gy
  • EBRT: 2 cm margin craniocaudally surrounding surgical wound
  • Brachytherapy: 45-70 Gy using 192 Ir wires loaded inside catheters placed in surgical wound; target volume was 2 cm craniocaudad of and 1.5 – 2 cm lateral to the surgical bed; catheters were loaded with the 192 Ir wires at 1-10 days after surgery (median 8 days)
  • Follow-up: median follow-up of 4.5 yrs
  • Pts were assessed for bone fracture, peripheral nerve damage, wound complications, neuromotor toxicity (weakness, impaired function, paralysis)

Results

• Disease Free Survival: 93% at 3 yrs; 92% at 5 yrs
• Local Recurrences: 17 of 214 pts (7.9%); median time to recurrence was 13 months
• Morbidity: 23 of 214 pts (10.7%)
  • • 7 bone fractures (3% at 5 yrs, average time to fracture was 31 months)
    • All 7 pts had brachytherapy + EBRT, all had dose >66 Gy
    • 4 of the 7 had >1 surgery prior to radiation
    • None of the clinical or treatment variables were significantly correlated with fractures in univariate analysis
    • All 7 pts were post-menopausal women (although gender was not significant in univariate analysis, p=0.3)
    • 5 pts with severe sclerosis (all had brachytherapy + EBRT, all had dose >70 Gy)
  • 3 pts with peripheral nerve damage
  • 8 pts with wound complications (2 required amputation, 3 were unable to complete EBRT due to wound complications)

Discussion

• The authors comment on the general advantages of brachytherapy in the treatment of STS, including decreased treatment time and cost, improved patient comfort, and ability to safely dose escalate within the tumor bed.
• Although the incidence of wound complications has been reported elsewhere to be higher following post-operative brachytherapy + EBRT compared to EBRT alone (48% vs. 16%), other studies have shown no difference (14% vs. 10%). The wound complication rate in this study was 3.5%, which was comparatively low.
• In other studies that have reported bone fractures after post-operative radiation for STS:
  • Fracture rates ranged from 5-8%
  • Higher rates were associated with brachytherapy boosts, periosteal stripping, and post-operative radiation
• In this study, it appeared that post-menopausal women were at higher risk, as were patients undergoing multiple surgeries prior to radiation
• Older age was generally associated with late toxicity (12/15 with late effects were over 50 years of age)

Comments

• Although the authors offer no explanation as to how the determination was made of treatment with EBRT alone vs. EBRT + brachytherapy, it can be assumed that those treated with the combination treatment were higher risk patients. This is evidenced by tumor grade (60% high grade in combination group vs. 43% high grade in EBRT alone group).
• Site of local recurrence was not specified in this study. The margins used for the EBRT portion of the treatment (2 cm craniocaudad) are relatively tight; some practitioners use 5-10 cm margins to prevent marginal miss. It would have been interesting to know where the recurrences occurred (i.e. inside or outside the radiation field).
• The authors advocate the use of brachytherapy in the treatment of STS, although the occurrence of nearly all of the late complications occurred in the patients treated with brachytherapy. Because brachytherapy delivers a higher dose of radiation in a shorter time to a smaller area, it is possible that the radiation dose rate impacted the late complication rate as much as the higher total dose. Notably, the authors observed 3 cases of peripheral nerve damage, a complication that is rarely seen with conventionally fractionated EBRT.