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Issues in Soft Tissue Sarcoma Management

Robert S. Bell, M.D., FRCSC
President and CEO of University Health Network
Princess Margaret Hospital
Toronto, ON

The past decade has seen limb sparing surgery become the standard of care for most patients with bone and soft tissue sarcomas. This has been accompanied by a growing emphasis on functional outcome and quality of life2,4,9. In soft tissue sarcoma (STS) treatment, radiotherapy (RT) has been instrumental in controlling local recurrence in the context of more limited surgery designed to preserve function2. However the combination of radiation and limb salvage has created its own set of complications and our investigations have concentrated on reducing complications of treatment and enhancing functional outcome.

STS tends to grow in centripetal fashion with active sarcoma cells at the periphery of the lesion that are capable of developing into a local recurrence if implanted in the surgical wound. Traditional limb salvage sarcoma surgery was designed to remove "wide or radical margins" of normal tissue surrounding the cancer in order to prevent implantation of these active cells2. STS originating in the extremities tend to grow close to critical structures such as major motor nerves and major vessels. Although the surgeon can generally remove a "wide margin" of muscle surrounding the sarcoma in the muscular limb compartments, close marginal dissection of major neurovascular structures increases the risk of local tumour recurrence8.

Radiation administered in conjunction with surgery is designed to eliminate tumour recurrence developing from cells that are left behind in the wound bed by "conservative, marginal" cancer surgery. This risk can be substantially reduced (to less than 10% risk of relapse at the local site of tumour origin) through the use of preoperative or postoperative adjuvant radiation8,14. Rare patients with very large or recurrent STS may require amputation to achieve local control of the cancer. However, the proportion of patients who need amputation has been reduced to less than 10% of cases in most sarcoma specialty centres10.

The traditional method of providing radiation in conjunction with surgery is to give radiation after surgery and postoperative wound healing is completed2,14. The benefit of postoperative radiation is that pathological assessment of the surgical specimen and the margins of surgical resection can be completed to ensure that radiation is indeed necessary. However, postoperative radiation treatment requires that the entire surgical wound be treated with radiation. This field size is much larger than the field size that would be provided with preoperative radiation13. In addition to the larger field size, the poorly oxygenated postoperative field requires a higher dose of radiation than the well-oxygenated tumour prior to surgery.

In contrast, the use of preoperative RT is associated with lower total radiation dose and a decrease in the volume of tissue exposed to radiation13. The reason for the decreased field size is that the radiation can be contoured to the tumour itself, maximizing treatment of the viable peripheral cells that can implant in the wound, rather treating the entire postoperative wound. Because the dose and field size are reduced, preoperative radiation may be associated with better functional outcomes and a lower fracture risk. However, giving radiation before surgery might also result in a much higher risk of wound healing complications after surgery.

We have undertaken a randomized controlled study comparing the outcomes of preoperative and postoperative radiation in patients who require combined management because of tumour size and location. The results of this study can be summarized as follows: 1) preoperative radiation results in a smaller radiation field than postoperative treatment; 2) preoperative treatment results in a doubling of wound complications following surgery; 3) postoperative treatment, because of its greater field size and higher dose, is associated with long-term edema, fibrosis and fracture risk5,12,14.

One of the ways that we can potentially reduce the risks of wound healing complications associated with preoperative radiation, while also maintaining the long-term advantages associated with lower dose and field size, is to use a new method of radiation therapy that can potentially reduce radiation impact on wound healing. Intensity modulated radiotherapy (IMRT) has the potential to reduce the surgical complication rate following preoperative radiation by protecting the superficial tissues that heal the wound as well as the underlying bone7. However, IMRT requires a collaborative team of surgeons, radiation oncologists and physicists expert in IMRT delivery and image guidance to permit extremely accurate targeted RT delivery to very selected volumes. To date, there is no long-term follow-up of patients treated with IMRT for soft tissue sarcoma and the risk of local recurrence using IMRT and surgery for STS remains to be determined.

Complementary biologic approaches may also modify these treatment-related toxicities. For example, in vitro testing of patients' normal fibroblasts has shown promise in predicting radiation sensitivity and identifying patients at high risk for development of adverse reactions such as fibrosis1. Cell therapy and tissue engineering approaches may soon provide real therapeutic wound healing opportunities for patients with sarcoma as well as other malignancies. For example, unirradiated dermal fibroblasts, bone marrow stromal cells, and biomaterials have been shown to improve radiation-impaired wound healing in animal models3, and these techniques may soon be used in practice.

Finally, it should be recognized that improvement of local management in STS only addresses one aspect of the risks posed by this cancer. Despite optimal local therapy, about one third of patients with STS in the extremity will develop lung metastases and most of these patients will die2. To this point, there is no clear evidence that administration of adjuvant chemotherapy in STS will enhance long-term survival and the chance of being cured of the disease6,15. However, recently, very effective targeted therapy specific to oncogenic molecular alterations found in gastrointestinal stromal tumours (a form of gastrointestinal sarcoma) has become available11. We remain hopeful that better understanding of the molecular alterations found in extremity STS will lead to similar success in reducing fatal outcomes for our patients.

References

  1. Akudugu J.M., Bell R.S., Catton C., et al. Wound healing morbidity in STS patients treated with preoperative radiotherapy in relation to in vitro skin fibroblast radiosensitivity, proliferative capacity and TGF-beta activity. Radiother Oncol 2006;78(1):17-26.
  2. Borden E.C., Baker L.H., Bell R.S., et al Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res. 2003 ;9(6):1941-56. Review.
  3. Dantzer D., Ferguson P., Hill R.P., et al. Effect of radiation and cell implantation on wound healing in a rat model. J Surg Oncol 2003;83(3):185-90.
  4. Davis A.M., O'Sullivan B., Bell R.S., et al. Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol 2002;20(22):4472-7.
  5. Davis A.M., O'Sullivan B., Turcotte R., et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75(1):48-53.
  6. Frustaci S., Gherlinzoni F., De Paoli A., et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol 2001;19(5):1238-47.
  7. Griffin A.M., Euler C.I., Sharpe M.B., et al. Radiation planning comparison for superficial tissue avoidance in radiotherapy for soft tissue sarcoma of the lower extremity. Int J Radiat Oncol Biol Phys 2006.
  8. Gerrand C.H., Wunder J.S., Kandel R.A., et al. Classification of positive margins after resection of soft-tissue sarcoma of the limb predicts the risk of local recurrence. JBone Joint Surg Br. 2001 ;83(8):1149-55.
  9. Gerrand C.H., Wunder J.S., Kandel R.A., et al. The influence of anatomic location on functional outcome in lower-extremity soft-tissue sarcoma. Ann Surg Oncol. 2004; 11(5):476-82.
  10. Ghert M.A., Abudu A., Driver N., et al. The indications for and the prognostic significance of amputation as the primary surgical procedure for localized soft tissue sarcoma of the extremity. Ann Surg Oncol. 2005 Jan;12(1):10-7.
  11. Heinrich M.C., Corless C.L., Demetri G.D., et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumour. J Clin Oncol 2003;21(23):4342-9.
  12. Holt G.E., Griffin A.M., Pintilie M., et al. Fractures following radiotherapy and limb-salvage surgery for lower extremity soft-tissue sarcomas. A comparison of high-dose and low-dose radiotherapy. J Bone Joint Surg Am 2005;87(2):315-9.
  13. Nielsen O.S., Cummings B., O'Sullivan B., et al. Preoperative and postoperative irradiation of soft tissue sarcomas: effect of radiation field size. Int J Radiat Oncol Biol Phys. 1991 Nov;21(6):1595-9.
  14. O'Sullivan B., Davis A.M., Turcotte R., et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002; 359(9325):2235-41.
  15. Sarcoma Meta-Analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 1997; 350(9092):1647-54.