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Editorial |
1 Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263
2 Department of Surgery, State University of New York at Buffalo, 462 Grider Street, Buffalo, New York 14214
Correspondence: 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{at}roswellpark.org.
Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less in human beings of whom they know nothing.– Voltaire (1694–1778)
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 limb-conserving multimodality therapy for extremity STS, local control rates are often upwards of 85%. Unfortunately, overall survival has not improved over the last 20 years.1 In contrast, local recurrence rates for RPS range from 20% to 50%.2–4 In addition, 40% of patients who are disease free at 5 years will develop a recurrence by 10 years.5 As opposed to extremity STS, most RPS patients succumb to local recurrence in the absence of distant metastases.2–4 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.6 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 double-edged 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 note, it also took these high-volume RPS institutions 7 years to accrue a total of 72 patients.
In June 2002, the first National Cancer Institute Sarcoma State of the Science meeting tried to identify the highest-priority clinical questions for STS. One of the major conclusions was as follows: "In patients with RPS, local recurrence is the major cause of mortality. A national trial evaluating the role of radiotherapy to enhance local control and survival is warranted and should be planned and carried out."7 In October 2003, the National Cancer Institute Sarcoma Progress Review Group also made several notable STS observations and recommendations: the participation of children in Children’s Oncology Group STS trials is an impressive 85%; several adult cooperative groups have sarcoma committees that develop competing studies; multiple logistic and regulatory issues prevent cross-group collaboration that could promote rapid accrual to trials; there is a need to strengthen sarcoma clinical research collaborations with the American College of Surgeons Oncology Group (ACOSOG), the Radiation Therapy Oncology Group (RTOG), and the Children’s Oncology Group; available trials at centers that are geographically convenient to patients are important; and there is a need for widespread publicity about STS trials to both practitioners and patients to improve clinical care and participation in prospective trials.8
In August 2004, ACOSOG opened Z9031, "a phase III randomized study of preoperative radiation plus surgery versus surgery alone for patients with RPS." The primary objective is to learn whether preoperative radiotherapy plus surgery improves progression-free survival as compared with surgery alone. Secondary objectives include assessing the toxicity and complications associated with preoperative radiotherapy/surgery, learning whether preoperative radiation increases the rate of microscopically complete surgical resection, and learning whether preoperative radiation increases the overall survival of patients with RPS. An equally important component is the correlative science section, in which blood and tumor samples will be collected to provide a better understanding of the natural history and response to therapy. The accrual goal is a fairly daunting 370 patients. There are currently 50 ACO-SOG sites across 27 states and Canada committed to the trial. The cooperative group mechanism also allows for RTOG institutions to participate.
Unfortunately, only seven patients have been enrolled onto Z9031 despite the best motivational and educational efforts of Dr. Pisters and ACOSOG. The critical question then becomes why. One reason might be the inability of patients to accept randomization to immediate versus delayed surgery, especially if they are currently symptomatic. Another explanation might be competing RPS trials, but there are none at a national level. The last cooperative group RPS trial, RTOG S-0124, "A Phase II Study of Multimodality Therapy for Primary and Recurrent Retroperitoneal Sarcomas" (with a much lower enrollment target of only 48 patients), closed because of poor accrual in July 2003. If competing, local trials are hindering enrollment, one must question whether or not limited, single-institution patient numbers will conclusively answer any meaningful scientific questions. One major reason for poor accrual is probably institutional or physician bias regarding the perceived merits or futility of radiation for RPS. A similar bias may have partially doomed the National Surgical Adjuvant Breast and Bowel Project R-03 trial of preoperative versus postoperative chemoradiation for rectal cancer. From a scientific standpoint, a lack of data to the contrary does not validate one’s opinion by default. The fate of Z9031 is uncertain at this time. As surgeons, we are the gatekeepers for the treatment of new patients with RPS, and ACOSOG is "our" cooperative group. If Z9031 fails because of poor accrual, we have no one to blame but ourselves.
There are in fact two things, science and opinion; the former begets knowledge, the latter ignorance.– Hippocrates (460–377 BC)
Received for publication October 13, 2005. Accepted for publication October 26, 2005.
REFERENCES
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  J. S. White, D. Biberdorf, L. M. DiFrancesco, E. Kurien, and W. Temple Use of Tissue Expanders and Pre-operative External Beam Radiotherapy in the Treatment of Retroperitoneal Sarcoma Ann. Surg. Oncol., February 1, 2007; 14(2): 583 - 590. [Abstract] [Full Text] [PDF]
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