Primary Tumor Necrosis Predicts Distant Control in Locally Advanced Soft-Tissue Sarcomas After Preoperative Concurrent Chemoradiotherapy

Purpose

Various neoadjuvant approaches have been evaluated for the treatment of locally advanced soft-tissue sarcomas. This retrospective study describes a uniquely modified version of the Eilber regimen developed at the University of Chicago.

Methods and Materials

We treated 34 patients (28 Stage III and 6 Stage IV) with locally advanced soft-tissue sarcomas of an extremity between 1995 and 2008. All patients received preoperative therapy including ifosfamide (2.5 g/m2 per day for 5 days) with concurrent radiation (28 Gy in 3.5-Gy daily fractions), sandwiched between various chemotherapy regimens. Postoperatively, 47% received further adjuvant chemotherapy.

Results

Most tumors (94%) were Grade 3, and all were T2b, with a median size of 10.3 cm. Wide excision was performed in 29 patients (85%), and 5 required amputation. Of the resected tumor specimens, 50% exhibited high (≥90%) treatment-induced necrosis and 11.8% had a complete pathologic response. Surgical margins were negative in all patients. The 5-year survival rate was 42.3% for all patients and 45.2% for Stage III patients. For limb-preservation patients, the 5-year local control rate was 89.0% and reoperation was required for wound complications in 17.2%. The 5-year freedom–from–distant metastasis rate was 53.4% (Stage IV patients excluded), and freedom from distant metastasis was superior if treatment-induced tumor necrosis was 90% or greater (84.6% vs. 19.9%, p = 0.02).

Conclusions

This well-tolerated concurrent chemoradiotherapy approach yields excellent rates of limb preservation and local control. The resulting treatment-induced necrosis rates are predictive of subsequent metastatic risk, and this information may provide an opportunity to guide postoperative systemic therapies.

Introduction

Soft-tissue sarcomas represent a heterogeneous group of tumors that account for approximately 1% of adult cancers (1). Most patients present with deep and large (>5 cm) tumors, both of which are unfavorable prognostic factors for disease control and survival (2).

Before the era of adjuvant therapy, locally advanced extremity sarcomas were generally managed with radical compartmental surgeries or amputations, often resulting in significant functional deficits 3, 4. The randomized study by Rosenberg et al.(5) showed in 1982 that limb-sparing surgery combined with adjuvant radiotherapy (RT) represents a well-tolerated alternative to amputation. Several subsequent randomized trials 6, 7 and retrospective series 4, 8, 9 have since validated this limb-sparing approach and have confirmed that adjuvant RT is an important component of therapy, at least for most high-grade tumors. The local control rate with this approach generally exceeds 85%, and many of the local recurrences that do occur can be surgically salvaged (4).

More recently, preoperative RT regimens have been substituted for postoperative RT, particularly in marginally resectable tumors. Advocates of preoperative RT suggest several potential advantages over postoperative therapy, including (1) tumor shrinkage that may enable less radical resection and (2) lower morbidity of RT because treatment volumes and doses can be safely reduced in the preoperative setting. A multicenter randomized trial in Canada directly compared preoperative and postoperative RT approaches, showing no significant differences in local control, metastasis, or survival rates at 5 years. There were somewhat more frequent wound complications in the preoperative RT arm; however, long-term toxicities (including fibrosis and joint stiffness) occurred more frequently in the postoperative group 10, 11.

In recent decades, chemotherapy 12, 13 and combined chemoradiotherapy (chemo/RT) 14, 15, 16, 17, 18, 19, 20, 21, 22 regimens have been explored for preoperative management of locally advanced tumors. The theoretic advantages of preoperative chemo/RT over RT alone include the possibility of better local tumor responses and earlier treatment of potential micrometastases. However, combined chemo/RT may also carry greater risks for toxicity, at least in the acute setting. Several such chemo/RT regimens have been developed, but none is presently considered superior. Doxorubicin has been the principal chemotherapy drug used in these trials, based on its known activity in the postoperative adjuvant setting (23). Ifosfamide is an additional drug with single-agent activity against sarcomas (24), and it too is commonly integrated into preoperative regimens.

A fairly common preoperative chemo/RT regimen was popularized by Eilber et al.14, 15, 16 at the University of California, Los Angeles. One of their early regimens included intra-arterial doxorubicin and sequentially delivered hypofractionated RT (35 Gy in 3.5-Gy fractions), followed by limb-sparing surgery (15). Despite the advanced presentations of tumors, all patients in this study avoided amputation and only 3% had local recurrences. However, complications of this regimen were frequent, with 23% of patients requiring reoperation, prompting modifications of RT dose. A subsequent trial with 17.5 Gy in 3.5-Gy fractions resulted in a higher rate of local failure, so the investigators ultimately settled on 28 Gy in 3.5-Gy daily fractions (14). The protocol was also modified to include intravenous administration of doxorubicin in place of intra-arterial administration, based on a randomized comparison that showed equivalent efficacy (16). More recently, ifosfamide was added to the regimen, resulting in higher tumor necrosis rates and better overall survival rates. The 5-year survival rate was 77% with a regimen containing ifosfamide compared with 64% without ifosfamide (14).

Another modern chemo/RT regimen uses mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) sandwiched sequentially around split-course standard-fractionation RT. A pilot study with this regimen yielded favorable outcomes and was reported by DeLaney et al.(18) from Massachusetts General Hospital (Boston, MA). This regimen was subsequently transitioned into a multi-institutional cooperative trial (Radiation Therapy Oncology Group [RTOG] 9514) that showed high rates of limb sparing (92%) and favorable rates of overall survival and local control (19).

The multidisciplinary sarcoma group at the University of Chicago has developed several uniquely modified versions of the Eilber regimen that involve hypofractionated RT given with sequential and concurrent chemotherapy. An earlier such regimen was evaluated in a Phase II multi-institutional trial involving 25 patients (20). A subsequent version of this regimen has since been our standard practice in patients who are marginal candidates for limb-preserving surgery. This regimen yields high rates of treatment-induced necrosis, limb preservation, and local control. In addition, we find that the treatment-induced tumor necrosis rate is significantly prognostic in terms of freedom from subsequent distant metastasis.