Preoperative radiotherapy for extremity soft tissue sarcoma; past, present and future perspectives on dose fractionation regimens and combined modality strategies

Abstract

Introduction: This critical review aims to summarize published data on limb sparing surgery for extremity soft tissue sarcoma in combination with pre-operative radiotherapy (RT).

Methods: This review is based on peer-reviewed publications using a PubMed search on the MeSH headings "soft tissue sarcoma" AND "preoperative radiotherapy". Titles and abstracts screened for data including "fraction size AND/OR total dose AND/OR overall treatment time", "chemotherapy", "targeted agents AND/OR tyrosine kinase inhibitors", are collated. Reference lists from some articles have been studied to obtain other pertinent articles. Additional abstracts presented at international sarcoma meetings have been included as well as information on relevant clinical trials available at the ClinicalTrials.gov website.

Results: Data are presented for the conventional regimen of 50-50.4Gy in 25-28 fractions in 5-6 of weeks preoperative external beam RT with respect to the regimen's local control probability compared to surgery alone, as well as acute and late toxicities. The rationale and outcome data for hypofractionated and/or reduced dose regimens are discussed. Finally, combination schedules with conventional chemotherapy and/or targeted agents are summarized.

Conclusion: Outside the setting of well-designed prospective clinical trials, the conventional 50Gy in 5-6week schedule should be considered as standard. However, current and future studies addressing alternative fraction size, total dose, overall treatment time and/or combination with chemotherapy or targeted agents may reveal regimens of equal or increased efficacy with reduced late morbidities.

Keywords: Chemotherapy; Combined modality treatment; Limb Soft Tissue Sarcoma; Preoperative radiotherapy; Surgery; Targeted agents.

Figure 1

A hypothetical local control probability curve, for simplification, calculated by: S = exp(− [αD + βD²]). In this graph, at 0 Gy the most unfavorable subgroup of patients (age above 50 years, sarcomas larger than 5 cm, resected with close or positive margins, and unfavorable histological subtypes as outlined in the text) in the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram [22] is chosen and at 50 Gy (preoperative) and at 66 Gy (postoperative) the outcomes of the NCIC SR-2 trial [1]. The three lines come forth from low to high α/β ratios calculations. The grey dots numbers 1, 2 and 3 represent the three consecutive Eilber studies [26, 27], number 4 comes from the Kosela study [31], and number 5 represents Temple’s data [28]. The biological equivalent dose (BED) of these dots are calculated assuming an α/β ratio of 4 Gy (5 × 3.5 Gy equals BED of 21,875 Gy, 8 × 3.5 Gy equals a BED of 35 Gy, 10 × 3.5 Gy equals a BED of 43,75 Gy, 5 × 5 Gy equals a BED of 37,5Gy, and 10 × 3 Gy equals a BED of 35 Gy). All points must be skewed to the left if these α/β ratios are higher than 4 Gy. All data derived from clinical studies and observations fairly match the calculated curves.

Figure 2

In Figure 2 two data sets on local control (shapes in black) and wound complications (shapes in grey) are combined. The black dots represent the local failures in the Eilber studies [26, 27] (see also Figure 1). The black oval summarizes the projected 5 years local failure probability from Table 2. The black striped line connects these outcome data and intends to intersect the y-axis at a local control achieved by surgery only as described in Table 2. The grey line, dots and oval represents the wound complication rate as a function of BED from the same references. The black and grey squares represent, respectively, the local failure- and wound complication probability as published by Kosela et al [31]. Finally, the black and grey triangles represent, respectively, the local failure- and wound complication probability as reported by Temple et al [28].