Preoperative chemotherapy and split-course radiation therapy for patients with localized soft tissue sarcomas: home run, base hit, or strike out?

Kraybill et al report results of Radiation Therapy Oncology Group (RTOG) trial 9514 —a phase II trial of preand postoperative modified mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy combined with preoperative split-course radiation (44 Gy given in two courses interdigitated with MAID cycles) for patients with stage III soft tissue sarcomas (STS) of the extremities and body wall. The authors and the RTOG are to be congratulated for completing the first American cooperative group trial for patients with localized STS in decades. In considering how this report affects the standard of care for patients with STS, however, several issues deserve close attention including patient selection, the toxicities of treatment, the effects of preoperative treatment on the extent of surgery, and the relative contributions of chemotherapy and radiation to the results. The eligibility criteria for RTOG 9514 included high-grade stage III STS of the extremity or body wall 8 cm in diameter. Without question, the study patients were at relatively high risk for systemic relapse, and preor postoperative chemotherapy designed to treat micrometastatic disease was worth considering given that 50% of such patients with large, ostensibly localized, high-grade STS have subclinical metastatic disease at presentation. However, eligibility criteria also included “clinical judgment of R0 surgical intent on completion of neoadjuvant chemotherapy and radiation therapy. ” It is not clear exactly what this means. Neither patients nor physicians have the prescience to know who will achieve a sufficient treatment-related response to enable macroscopically and microscopically complete surgical resection (R0 resection), but patients with localized disease considered operable at diagnosis are more likely to be able to undergo limb-sparing R0 resection than are patients with locally advanced disease not immediately operable with commonly utilized limb-sparing approaches. The “R0 surgical intent” criterion therefore raises questions about the patients’ extent of disease. Although many patients enrolled in RTOG 9514 probably had localized disease, it is likely that some participating physicians selected patients for this protocol who had locally advanced disease in the hope that treatment-related response would improve operability. Thus, it would be of great interest to patients and clinicians to know if patients who responded to preoperative therapy had a change in the scope of planned surgery. A significant alteration in the scope of surgery remains an important short-term potential advantage of preoperative chemotherapy or radiation therapy that is independent of the long-term efficacy of such treatment. There is no question that a patient who avoids amputation as a result of a clinically significant chemotherapyand/or radiationrelated response experiences a clinical benefit regardless of whether the therapy impacts overall survival. Thus, an important clinical question that remains is, how often does clinically meaningful down staging occur with preoperative treatment? The issue of clinically meaningful down staging with preoperative treatment was addressed in part in reports from The University of Texas M.D. Anderson Cancer Center (Houston, TX). In 1997, we reported the results of preoperative anthracycline-based chemotherapy in 76 consecutive patients with stage III STS (median tumor size, 10.0 cm). Major radiological responses (confirmed by retrospective review of imaging studies) occurred in 27% of patients, while confirmed radiologic disease progression occurred in 30% of patients. However, this study did not allow us to determine what fraction of responding patients had experienced a primary tumor response significant enough to reduce the scope of planned surgery or what fraction of the 30% of patients who experienced local tumor progression had the scope of planned surgery increased as a consequence of local disease progression during preoperative treatment. This question was addressed in a 2002 report of a nonoverlapping cohort of 65 patients treated with anthracyclineand/or ifosfamide-based preoperative chemotherapy in which we observed a similar 34% response rate and 26% rate of disease progression. In this second report, the impact of preoperative chemotherapy on the scope of anticipated surgery was assessed by a panel of three sarcoma surgeons blinded to the operative treatment rendered and to patient outcome. Preoperative treatment resulted in a decrease in the scope of anticipated surgery in 13% of patients, while 9% had disease progression significant enough to increase the scope of surgery. Apart from this study, the literature evaluating clinically meaningful down staging is limited, and the ambiguity in the eligibility criteria in the report from Kraybill et al does not allow us to shed further light on this important issue. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 4 FEBRUARY 1 2006