Soft tissue sarcomas (STS) are rare, but potentially lethal, extraskeletal mesenchymal neoplasms. It is estimated that approximately 12,000 cases of STS are reported annually in the United States, with 3,500 STS deaths. Few randomized controlled trials (RCTs) have been conducted since the previous issue of this publication. The current understanding of STS biology and, hence, ability to provide safe, effective therapy is predicated upon seminal trials performed in the 1980s and 1990s. The authors briefly summarize the trials presented in the previous issue and then critically assess the more recent publications that have addressed the management of STS.
Soft tissue sarcomas (STS) are a heterogeneous group of rare but potentially lethal, extraskeletal mesenchymal neoplasms. Although the absolute incidence is unknown, it is estimated that approximately 12,000 cases of STS are reported annually in the United States, with 3,500 STS deaths. The rarity of these diseases explains, in large part, why few randomized controlled trials (RCTs) have been conducted since the previous issue of this publication. The current understanding of STS biology and, hence, ability to provide safe, effective therapy is predicated upon seminal trials performed in the 1980s and 1990s. The authors briefly summarize the trials presented in the previous issue and then critically assess the more recent publications that have addressed the management of STS. This review does not include pediatric sarcomas or gastrointestinal stromal tumors, the latter of which are covered in a separate article.
Surgery
The original RCT addressing the surgical management of STS had a profound impact, despite being small. Rosenberg and colleagues reported that when compared with amputation, wide excision with external beam radiation therapy was associated with equivalent 5-year disease-free and overall survival. Demonstration of equivalence for limb preservation clearly has had important functional and quality of life implications for patients with extremity STS. This trial illustrated that while local recurrence may be associated with distant metastases and death from disease, the relationship is not necessarily causative. Recent retrospective studies have provided additional guidance for our surgical treatment of STS.
Radiation therapy
The impact of postoperative radiation therapy on STS was largely defined by two RCTs. Pisters and colleagues reported that adjuvant brachytherapy decreased local recurrence following resection of extremity STS, with the greatest benefit being conferred to patients with high-grade tumors. Yang and colleagues demonstrated the effectiveness of external beam radiation in limiting local recurrence for both high and low-grade extremity STS. A more recent report addressed preoperative external beam radiation therapy. O’Sullivan and colleagues reported a multicenter randomized trial that demonstrated that neoadjuvant external beam radiation therapy is associated with a higher rate of complications than postoperative adjuvant therapy. A subsequent article from the same authors demonstrated that, despite the higher rate of wound complications, neoadjuvant radiation therapy leads to better functional outcomes. A small survival advantage was associated with preoperative radiation therapy, yet there was no difference in either local or distant recurrence.
Radiation therapy
The impact of postoperative radiation therapy on STS was largely defined by two RCTs. Pisters and colleagues reported that adjuvant brachytherapy decreased local recurrence following resection of extremity STS, with the greatest benefit being conferred to patients with high-grade tumors. Yang and colleagues demonstrated the effectiveness of external beam radiation in limiting local recurrence for both high and low-grade extremity STS. A more recent report addressed preoperative external beam radiation therapy. O’Sullivan and colleagues reported a multicenter randomized trial that demonstrated that neoadjuvant external beam radiation therapy is associated with a higher rate of complications than postoperative adjuvant therapy. A subsequent article from the same authors demonstrated that, despite the higher rate of wound complications, neoadjuvant radiation therapy leads to better functional outcomes. A small survival advantage was associated with preoperative radiation therapy, yet there was no difference in either local or distant recurrence.
Chemotherapy
The level 1 chemotherapy trials summarized in the previous issue indicated some improvements in recurrence-free intervals or response rates, but not survival. A recent meta-analysis which included 1953 patients from 18 trials indicated significant recurrence-free and survival advantages associated with adjuvant doxorubicin-based regimens ( Table 1 ). The small absolute recurrence and survival benefits (3%–10%) presented in the meta-analysis must be tempered against the known toxicities of doxorubicin-based systemic regimens. Furthermore, the vast majority of the individual trials included in the meta-analysis failed to demonstrate a significant survival benefit.
| Outcome | OR (95% CI) | p | ARR (95% CI) | NNT |
|---|---|---|---|---|
| Local recurrence | 0.73 (0.56–0.94) | 0.02 | 3% (0%–7%) | 25 |
| Distant recurrence | 0.67 (0.56–0.86) | <0.01 | 9% (5%–14%) | 12 |
| Overall recurrence | 0.67 (0.56–0.82) | <0.01 | 10% (5%–15%) | 10 |
| Overall survival | 0.77 (0.64–0.93) | 0.01 | 6% (2%–11%) | 17 |
In a small RCT that closed after 12 years because of poor accrual, Petrioli and colleagues found a statistically significant recurrence-free advantage for epirubicin-based postoperative chemotherapy, but no significant difference with respect to overall survival. A single trial with a small number of patients found no benefit to the addition of intraperitoneal chemotherapy following cytoreduction for peritoneal sarcomatosis. Mace and colleagues showed that, in a small group of patients receiving ifosfamide for STS, a regimen incorporating oral mesna as opposed to exclusively intravenous (IV) mesna was as effective in providing uroprotection. In a large phase III trial, Lorigan and colleagues found that single agent ifosfamide should not replace doxorubicin as the first-line agent for advanced STS. A randomized phase II trial of neoadjuvant doxorubicin with ifosfamide for high-risk STS demonstrated that preoperative therapy afforded no survival or recurrence benefit compared with surgery alone.
Summary
The lessons learned from the trials discussed above have influenced our management of STS in meaningful ways. Limb-sparing surgery offers an equivalent chance of cure and a clear functional advantage when compared with amputation for extremity STS. Adjuvant radiation therapy for extremity STS significantly decreases the chance of local recurrence. Preoperative radiation therapy increases the risk of wound complications but is associated with better functional outcomes than postoperative radiation treatment. The decrease in local recurrence afforded by radiation therapy does not affect survival time because most patients who succumb to extremity STS die from disseminated disease. Local recurrence is an important cause of death in cases of retroperitoneal sarcoma, yet the evidence supporting a role for radiation therapy in these cases is lacking. Trials addressing the impact of modern, more targeted delivery of external beam radiation for retroperitoneal sarcoma are warranted. With regard to systemic therapy, the body of evidence does not indicate a compelling long-term survival benefit for any systemic regimen. More sophisticated predictors of response are needed, in addition to the identification of novel targets and agents. Slight modifications of approaches already proven to have marginal or no survival benefit will not lead to meaningful progress.
Future directions
The rarity of soft tissue sarcomas makes conducting RCTs for these diseases extraordinarily challenging. Multi-institutional trials are needed to define the role of neoadjuvant chemotherapy and radiation therapy for high-risk soft tissue sarcomas, including those arising in the retroperitoneum. More importantly, our increasingly sophisticated understanding of the biologic differences among soft tissue sarcoma subtypes, along with tumor heterogeneity within subtypes, should be incorporated into treatment strategies. The success of future trials for soft tissue sarcoma chemotherapy may depend, in large part, on our ability to define inclusion criteria to focus on more biologically homogeneous groups of patients.
Level I evidence: randomized clinical trials
1. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. O’Sullivan B, Davis AM, Turcotte R, et al. Lancet 2002;359:2235–41.
Hypothesis: The use of preoperative radiation therapy would be associated with a higher rate of wound complications.
| # Patients Randomized | Study Groups | Stratification | Significance Demonstrated | Change Identified in Trial |
|---|---|---|---|---|
| 190 | Preoperative (N=94) | Tumor size (10cm) | Yes | 18% absolute increase in wound complication rate with neoadjuvant therapy |
| Postoperative (N=96) |
Published abstract: BACKGROUND: External-beam radiotherapy (delivered either preoperatively or postoperatively) is frequently used in local management of sarcomas in the soft tissue of limbs, but the two approaches differ substantially in their potential toxic effects. We aimed to determine whether the timing of external-beam radiotherapy affected the number of wound healing complications in soft-tissue sarcoma in the limbs of adults. METHODS: After stratification by tumor size (≤10 cm or >10 cm), we randomly allocated 94 patients to preoperative radiotherapy (50 Gy in 25 fractions) and 96 to postoperative radiotherapy (66 Gy in 33 fractions). The primary endpoint was rate of wound complications within 120 days of surgery. Analyses were per protocol for primary outcomes and by intention to treat for secondary outcomes. FINDINGS: Median follow-up was 3·3 years (range 0·27–5·6). Four patients, all in the preoperative group, did not undergo protocol surgery and were not evaluable for the primary outcome. Of those patients who were eligible and evaluable, wound complications were recorded in 31 (35%) of 88 in the preoperative group and 16 (17%) of 94 in the postoperative group (difference 18% [95% CI 5–30], P = 0·01). Tumor size and anatomic site were also significant risk factors in multivariate analysis. Overall survival was slightly better in patients who had preoperative radiotherapy than in those who had postoperative treatment ( P = 0·0481). INTERPRETATION: Because preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy, the choice of regimen for patients with soft-tissue sarcoma should take into account the timing of surgery and radiotherapy, and the size and anatomic site of the tumor. (Copyright Elsevier 2002.)
Editor’s summary and comments: The principal question posed by the authors was adequately addressed. Patients who received radiation therapy before surgery had a clinically and statistically significant increase in the rate of wound complications. Forty-five percent of the patients in the neoadjuvant group who developed a wound complication required reoperation for management. Lower extremity sites and tumors larger than 10cm were associated with a greater risk of wound complications. The two groups did not differ with respect to recurrence- or progression-free survival. A small 3-year overall survival advantage ( P = .05) was noted in the preoperative group (85%) compared with the postoperative group (72%). The short duration of follow-up and the use of overall survival as an endpoint warrant caution because 19% of the deaths in the postoperative group were not due to disease, compared with only 7% in the preoperative group. The authors also note that the study was not adequately powered to detect this difference in a secondary endpoint such as overall survival. In a follow-up article, patients who received postoperative radiation therapy were found to have significantly worse functional outcomes with respect to fibrosis, joint stiffness, edema, and functional scores.
2. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Petrioli R, Coratti A, Correale P, et al. Am J Clin Oncol 2002;25:468–73.
Hypothesis: The use of epirubicin with or without ifosfamide after local therapy for STS would improve the disease-free interval and overall survival duration.
| # Patients Randomized | Study Groups | Stratification | Significance Demonstrated | Change Identified in Trial |
|---|---|---|---|---|
| 88 | Epiriubicin ± Ifosfamide (N=45) | None | Yes | Absolute DFS benefit at 5 years of 25% ( P = .01) with a trend toward improved OS ( P = .06) |
| Observation (N=43) |
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