Preoperative multimodality treatment of localized soft tissue sarcoma: addition through subtraction?

In this issue of Annals of Surgical Oncology, Mack and colleagues from the Tom Baker Cancer Center at The University of Calgary report their results with preoperative intravenous or intra-arterial doxorubicin and short-course, high-dose-per-fraction (10 fractions of 3 Gy each) radiotherapy followed by wide local resection for selected patients with extremity soft tissue sarcomas. The authors report remarkably low treatment-related complication rates, and in the subset of patients who underwent preoperative chemoradiation followed by macroscopically and microscopically complete (R0) surgical resection, a 97% 5-year local control rate was observed. Can this regimen serve as a therapeutic maquette, or are these results best regarded as aleatoric, as are many findings in clinical research? This report raises a number of important issues that warrant further consideration and discussion. These include the important issues of patient selection, complication rates, radiation fractionation and schedule, and the relative contributions of chemotherapy, radiation, and patient selection to these results. Historical background is relevant in understanding the rational underpinning of the treatment approach used by Mack and colleagues. This approach has its roots in the protocols developed two decades earlier at the University of California, Los Angeles (UCLA) by Eilber et al. The UCLA group adopted large-dose-per-fraction preoperative radiotherapy (10 fractions of 3.5 Gy each) to overcome the putative radioresistance of soft tissue sarcomas. The investigators were influenced in their regimen design by the observation that irradiation of some melanoma cell lines resulted in a large initial shoulder on the cell survival curve, although later evidence suggested that this may not be consistent. Nonetheless, the potential radioresistance of melanoma and, by extension, sarcoma was attributed to the tumor cells capacity for repair of sublethal damage implied by this shoulder. This preclinical speculation led to pilot studies performed in patients with soft tissue sarcoma by Eilber et al. and others that established the relative toxicities and local control rates associated with short-course, highdose-per-fraction radiation and concurrent intraarterial or intravenous anthracycline-based chemotherapy. On the basis of these pilot studies, a handful of centers, including the Tom Baker Cancer Center, adopted this approach as their standard therapy for patients with localized soft tissue sarcomas. Patient selection is one of the many issues that should be considered in the interpretation of the Tom Baker Cancer Center experience with the modified UCLA regimen. In the abstract and introduction, Mack and colleagues report that their chemoradiation approach was used in all patients who presented with soft tissue sarcomas of the extremity and trunk between 1984 and 1996, and their results are presented as a consecutive series. However, in the Methods section, the authors clarify that they excluded patients who were believed to have tumor involvement of major nerves or bone. They do not indicate what specific clinical or Received June 2, 2005; accepted June 3, 2005; published online June 29, 2005. Address correspondence and reprint requests to: Peter W. T. Pisters, MD, FACS; E-mail: ppisters@mdanderson.org