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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 549-551 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.3026
Preoperative Chemotherapy and Split-Course Radiation Therapy for Patients With Localized Soft Tissue Sarcomas: Home Run, Base Hit, or Strike Out?Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Kraybill et al1 report results of Radiation Therapy Oncology Group (RTOG) trial 9514—a phase II trial of pre- and 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 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 chemotherapy- and/or radiation- related 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).2,3 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).2 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 anthracycline- and/or ifosfamide-based preoperative chemotherapy in which we observed a similar 34% response rate and 26% rate of disease progression.3 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.1 The toxicities of the modified MAID chemotherapy and split-course radiation regimen used in RTOG 9514 are candidly described by the authors as significant. Grade 4 hematologic and nonhematologic toxicities occurred in 78% and 19% of patients, respectively. Furthermore, five patients (8%) had treatment-related amputation (n = 2) or died of treatment-related complications (n = 1) or of acute myelogenous leukemia attributed by the authors to the treatment (n = 2). Toxic therapy is more easily justified and accepted by patients and physicians in the settings of (1) uniformly poor outcomes without treatment (such as in acute leukemia or pancreatic adenocarcinoma); and/or (2) an unequivocal return on the toxicity investment. Neither condition can be unequivocally established for the patient population studied in this trial. Patients with American Joint Committee on Cancer stage III STS have an approximate 50% 5-year overall survival rate4 that has not changed significantly in decades.5 Thus, it is important to bear in mind that one of every two patients will live at least 5 years without pre- or postoperative chemotherapy. This half of the patient population incurs the short- and long-term risks of chemotherapy treatment without the possibility of clinical benefit. And what about the second condition—what is the return on the toxicity investment (ignoring for the time being other arguably important matters such as quality of life)? Kraybill et al report 3-year local regional failure and disease-free survival rates (when amputation was not considered a treatment failure) of 10.1% (95% CI, 2.3% to 17.8%) and 59.7% (95% CI, 46.2% to 70.8%), respectively. Even given the considerable limitations of any form of comparison to other reports, it is fair to say that these treatment results do not appear to be superior to what can be achieved by local therapy alone.6,7 Is the considerable toxicity worthwhile in light of what appears to be a small therapeutic ratio? If nearly four in five patients experiences one or more grade 4 toxicities, and 8% of patients either undergo amputation or die because of the treatment, we need unequivocal home run results to offset the considerable risks for treatment-related morbidity and death. Given the modest outcome data reported, it is difficult to consider this approach to be a form of therapeutic maquette from which to build and therefore difficult to regard this trial as a base hit for patients with extremity STS. The relative contributions of anthracycline-based chemotherapy and radiation treatment to these results also warrant careful thought. Small, single-institution, randomized trials have demonstrated improved local control with the addition of radiation to surgical resection for patients with extremity STS.8,9 However, the evidence for anthracycline-based chemotherapy is considerably less firm. A meta-analysis of a series of predominantly small, randomized trials of adjuvant doxorubicin-based chemotherapy suggested a 4% overall survival benefit for the subset of patients in the meta-analysis with extremity STS.10 However, three small (arguably underpowered), randomized trials performed using modern chemotherapy regimens and doses reported after the meta-analysis were negative.11-13 At the time of initial publication with short-term follow-up, one of these trials showed improved overall survival for chemotherapy treated patients.14 However, 4-year metastasis-free survival rates in the chemotherapy and control groups were identical and, as predicted,15 with longer patient follow-up the overall survival rates in the chemotherapy and control groups are no longer statistically significant.13 A retrospective cohort analysis of the combined experience of The University of Texas M.D. Anderson and Memorial Sloan-Kettering Cancer Centers with anthracycline-based pre- or postoperative chemotherapy for stage III extremity STS revealed a statistically significantly inferior overall survival rate in patients who received chemotherapy,7 while an analysis of the combined Dana-Farber Cancer Center (Boston, MA) and Memorial Sloan-Kettering Cancer Center (New York, NY) experience with anthracycline-based preoperative chemotherapy demonstrated a survival improvement only for the subset of patients with tumors greater than 10 cm.7,16 There is widespread disagreement on how to interpret these results. What seems clear and indubitable, however, are four points: (1) anthracycline-based pre- or postoperative chemotherapy has short- and long-term toxicities; (2) more chemotherapy is more toxic17; (3) the clinical benefit from adjuvant anthracycline-based chemotherapy—if it exists—is small, and the therapeutic ratio is thus very small; and (4) new treatment approaches are desperately needed. Given the substantial toxicities attributed to anthracycline-based chemoradiotherapy in Kraybill et al report and the open question of whether such treatment provides a durable overall survival benefit, it is difficult to make a compelling case for routine administration of anthracycline-based chemotherapy for patients similar to those included in RTOG 9514. We are left then with the conundrum of how to make meaningful progress against a rare disease like STS. Two points are critically important. First, collaborations are essential, including international collaborations, cooperative group efforts such as RTOG 9514, and collaborations with industry to study new agents. Second, given the unique natural history and biology of most subtypes of STS, we must move to develop trials focused on individual tumor subtypes. In essence, we must become splitters and not lumpers. Without question, base hits for patients with STS will require improved understanding of sarcoma biology, new drugs, histology-specific trials, improved industry and government support, and novel forms of collaboration. Author's Disclosures of Potential Conflicts of Interest The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Author Contributions
REFERENCES
1. Kraybill WG, Harris JA, Spiro IJ, et al: RTOG 9514: A phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall. J Clin Oncol 24:619-625, 2006 2. Pisters PWT, Patel SR, Varma DGK, et al: Preoperative chemotherapy for stage IIIB extremity soft tissue sarcoma: Long-term results from a single institution. J Clin Oncol 15:3481-3487, 1997 3. Meric F, Hess K, Varma DG, et al: Radiographic response to neoadjuvant chemotherapy is a predictor of local control and survival in soft tissue sarcomas. Cancer 95:1120-1126, 2002[CrossRef][Medline] 4. Brennan MF, Singer S, Maki RG, et al: Sarcomas of the soft tissue and bone, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott, Williams, and Wilkins, 2004, pp 1581-1637 5. Weitz J, Antonescu CR, Brennan MF: Localized extremity soft tissue sarcoma: Improved knowledge with unchanged survival over time. J Clin Oncol 21:2719-2725, 2003 6. O'Sullivan B, Davis AM, Turcotte R, et al: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomized trial. Lancet 359:2235-2241, 2002[CrossRef][Medline] 7. Cormier JN, Huang X, Xing Y, et al: Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: Chemotherapy-associated outcomes. J Clin Oncol 22:4567-4574, 2004 8. Pisters PWT, Harrison LB, Woodruff JM, et al: A prospective randomized trial of adjuvant brachytherapy in the management of low grade soft tissue sarcomas of the extremity and superficial trunk. J Clin Oncol 12:1150-1155, 1994 9. Yang JC, Chang AE, Baker AR, et al: A randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16:197-203, 1998 10. Tierney JF: Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Lancet 350:1647-1654, 1997[CrossRef][Medline] 11. Brodowicz T, Schwameis E, Widder J, et al: Intensified adjuvant IFADIC chemotherapy for adult soft tissue sarcoma: A prospective randomized feasibility trial. Sarcoma 4:151-160, 2000 12. Petrioli R, Coratti A, Correale P, et al: Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol 25:468-473, 2002[CrossRef][Medline] 13. Frustaci S, De Paoli A, Bidoli E, et al: Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology 65:80-84, 2003[CrossRef][Medline] 14. 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 19:1238-1247, 2001 15. Bramwell VH: Adjuvant chemotherapy for adult soft tissue sarcoma: Is there a standard of care? J Clin Oncol 19:1235-1237, 2001 16. Grobmyer SR, Maki RG, Demetri GD, et al: Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol 15:1667-1672, 2004 17. Worden FP, Taylor JM, Biermann JS, et al: Randomized phase II evaluation of 6 g/m2 of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor (GCSF) compared with 12 g/m2 of ifosfamide plus doxorubicin and G-CSF in the treatment of poor-prognosis soft tissue sarcoma. J Clin Oncol 23:105-112, 2005 Related Article
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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8 cm in diameter. Without question, the study patients were at relatively high risk for systemic relapse, and pre- or 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."
