At the crossroads for retroperitoneal sarcomas: the future of clinical trials for this "orphan disease".

In 1993, the Office of Rare Diseases was established within the National Institutes of Health to ‘‘stimulate and coordinate research on rare diseases.’’ The Office of Rare Diseases defines a rare or orphan disease as ‘‘a condition affecting fewer than 200,000 persons in the United States.’’ Collectively, soft tissue sarcomas (STS) are on the official list. At only 10% to 15% of all STS, retroperitoneal sarcomas (RPS) truly have orphan status. Therefore, how does one acquire evidence-based treatment information on a low-incidence tumor such as RPS? One could simply extrapolate from what is known about the larger group of extremity STS, but this would not be entirely correct. In the era of limbconserving multimodality therapy for extremity STS, local control rates are often upwards of 85%. Unfortunately, overall survival has not improved over the last 20 years. In contrast, local recurrence rates for RPS range from 20% to 50%. 4 In addition, 40% of patients who are disease free at 5 years will develop a recurrence by 10 years. As opposed to extremity STS, most RPS patients succumb to local recurrence in the absence of distant metastases. 4 Therefore, improved local control for RPS might translate into better overall survival. To complicate matters, the challenges of administering radiotherapy for RPS are greater than for extremity STS because of the proximity of vital gastrointestinal or neural structures. By combining two well-designed but somewhat dissimilar trials, Pawlik et al. have made a small step toward improving the treatment of RPS. They showed that 89% of patients were able to complete preoperative radiation. For the 57 patients who underwent potentially curative surgery, the R0/R1 resection rate was 95%, the 5-year local recurrence free survival rate was 60%, and only 20% of patients experienced some component of distant failure. Ten patients developed distant metastases during preoperative radiation and were spared the otherwise noncurative operation they would have received had they undergone surgical resection immediately after diagnosis. However, preoperative therapy may be a doubleedged sword. Three patients initially believed to have resectable tumor could not undergo complete gross resection at the time of surgical exploration. Things might have been different had surgery not been delayed for several weeks as a result of radiation. The findings of this study are provocative but reinforce the need for a well-designed randomized, prospective trial to identify the role of preoperative radiation for primary RPS. Confounding variables included the following: 25% of their RPS were recurrent, 28% patients received <45 Gy of radiation (less likely to have a significant biologic effect on the tumor), an intraoperative or postoperative radiation boost was used in 60% of the surgical patients, and some patients received systemic chemotherapy. Of Received October 13, 2005; accepted October 26, 2005; published online February 28, 2006. Address correspondence and reprint requests to: John M. Kane III, MD, Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; E-mail: john.kane@ roswellpark.org.