Neoadjuvant Therapy for Soft-Tissue Sarcomas

Soft-tissue sarcomas encompass a diverse group of rare neoplasms that can occur in any compartment of the body. They provide a therapeutic challenge to clinicians because of their typically large size at presentation, as well as their potentially close proximity to critical structures (ie, blood vessels, nerves). Even when a macroscopically complete resection with negative microscopic margins is achieved, local and distant recurrence rates are significant. Optimal management of patients with soft-tissue sarcomas should involve a multidisciplinary approach, with involvement of a surgical oncologist in addition to medical and radiation oncologists. Utilization of neoadjuvant therapies potentially provides local and distant control. The use of neoadjuvant therapy is influenced by the tumor biology (histologic subtype and grade), as well as the tumor location, and remains an area of controversy. The aim of this review is to discuss current neoadjuvant treatment options for soft-tissue sarcomas.

Introduction

Soft-tissue sarcomas are a rare and heterogeneous group of tumors of mesenchymal origin. With over 70 different histologic subtypes, and only approximately 12,000 new diagnoses a year, there is an inherent challenge to defining management protocols in the absence of large prospective studies or randomized controlled trials (RCTs).[1] Although these tumors most commonly occur in the extremities and retroperitoneum, they can occur anywhere in the body. A macroscopically complete resection with negative microscopic margins (R0 resection) remains the standard of care for localized soft-tissue sarcomas as the only potentially curative treatment. However, the location of the tumor can make this very difficult to achieve, and even in the event of a complete resection, local recurrence rates range from 22% to 84%.[2-6] In extremity sarcomas, emphasis is placed on function-preserving limb conservation in addition to negative resection margins. Retroperitoneal sarcomas provide a challenge to clinicians because of their typically late presentation and subsequent large size at time of presentation. They frequently involve multiple organs and can occur in close proximity to vital neurovascular structures.

The anatomic complexity and significant recurrence rates of soft-tissue sarcomas, even in the setting of an R0 resection, has necessitated investigation of neoadjuvant therapies to improve both local and systemic control. There are several benefits to this approach; neoadjuvant therapy allows assessment of tumor response and can facilitate an R0 resection. Additionally, this approach can eradicate micrometastases early in the disease course and may lead to improved compliance, since patients are not recovering from potential operative morbidities while receiving treatment.

Management of soft-tissue sarcomas is not only influenced by histologic subtype, but by recurrence patterns based on anatomic location. Mortality in patients with retroperitoneal sarcomas is more often secondary to local failure as opposed to distant metastasis, whereas distant recurrence is the primary cause of mortality for extremity soft-tissue sarcomas.[7] The location (extremity/trunk vs retroperitoneum) determines the feasibility of radiation therapy (RT) due to risk of injury to surrounding structures/organs. The diverse histologies of soft-tissue sarcomas with subsequent complex biologic behaviors make certain histologic subtypes more susceptible than others to chemotherapy and RT. Given the complexity of treatment for soft-tissue sarcomas, we recommend a multidisciplinary approach at specialized sarcoma centers in order to improve long-term survival, decrease recurrence risk, and optimize surgical outcomes.

Extremity and Trunk Sarcomas

Extremity sarcomas account for over 50% of soft-tissue sarcomas. Historically, the mainstay of treatment for extremity soft-tissue sarcomas was amputation. Results from a rare phase III trial on sarcoma surgery by Rosenberg et al dramatically changed the standard of care, with a shift toward limb sparing and use of adjuvant therapies.[8] Function-preserving limb-conserving resection with negative microscopic margins is now considered the standard of care. The goal of neoadjuvant therapy is to improve both local and-depending on modality-distant control. Risk of recurrence for soft-tissue sarcomas will vary based on histologic subtype, tumor grade, and size. The risk of metastatic disease increases as primary tumor size increases. For high-grade tumors, the risk of metastatic disease for tumors 5.1 to 10 cm, 10.1 to 15 cm, and 15.1 to 20 cm is 34%, 43%, and 58%, respectively.[9] The potential benefit from neoadjuvant therapies, however, must be weighed against the risk of disease progression due to delayed resection during treatment, as well as an increased risk of postoperative complications.

Chemotherapy

Several single- and multi-institution studies investigating the use of chemotherapy followed by surgery have reported inconsistent findings using doxorubicin-based chemotherapy. Although neoadjuvant chemotherapy provides a survival benefit in some childhood soft-tissue sarcomas (ie, rhabdomyosarcoma, Ewing sarcoma), its utility in most other histologic subtypes remains unclear. Given the lack of data supporting the use of neoadjuvant chemotherapy followed by surgery, this approach remains controversial.

In 2001, the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group conducted a randomized phase II study investigating the outcomes of neoadjuvant chemotherapy.[10] In this study, 134 patients with high-risk soft-tissue sarcomas of the extremity, trunk, and pelvis were randomized to undergo surgery alone or to receive 3 cycles of every-3-weeks doxorubicin (50 mg/m²) and ifosfamide (5 g/m²) before surgery. High-risk tumors were defined as those ≥ 8 cm and of any grade, grade 2/3 tumors < 8 cm, grade 2/3 locally recurrent tumors, or grade 2/3 tumors with inadequate surgery performed in the previous 6 weeks and therefore requiring additional resection. Of 49 patients assessed for disease response, complete response was noted in 4 patients (8%), partial response in 10 patients (20%), stable disease in 26 patients (53%), and disease progression in 9 patients (18%) at the time of surgery. Limb salvage was achieved in 88% of patients, with 6 patients in the surgery-alone group and 9 patients in the neoadjuvant chemotherapy group undergoing amputation, which was in concordance with the originally planned surgery at the time of randomization. All originally planned amputations were performed, and no patients planned for limb salvage required amputation due to disease progression during neoadjuvant treatment. An R0 resection was obtained in 88% and 91% of patients in the surgery-alone group and neoadjuvant therapy group, respectively. The most common complication was superficial infection, which was seen in 14% of patients in each group. With a median follow-up of 7.3 years, there was no difference in 5-year disease-free survival (DFS, 52% vs 56%; P = .35) or overall survival (OS, 64% vs 65%; P = .22) between the surgery-alone and neoadjuvant therapy cohorts. The authors concluded that delaying surgery to administer neoadjuvant chemotherapy did not negatively affect surgical outcomes or postoperative complication rates; however, there was no survival benefit observed with neoadjuvant chemotherapy. Unfortunately, due to slow accrual for this study, the authors were unable to expand into a larger phase III trial.

Grobmyer et al reported on the role of neoadjuvant chemotherapy in order to identify a cohort of high-risk patients that could potentially benefit.[11] This study retrospectively analyzed 356 patients who had primary ≥ 5 cm, high-grade, and deep-extremity sarcomas, taken from prospective databases from both Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Patients who received a mean of 3 cycles of neoadjuvant treatment consisting of doxorubicin (75 mg/m²), ifosfamide (6 to 9 g/m²), and mesna (AIM regimen) were compared with similar patients who did not receive chemotherapy. The 3-year overall disease-specific survival (DSS) was 73%. When stratified by histology, size of primary tumor, and age, the use of neoadjuvant chemotherapy was associated with a significant improvement in DSS (hazard ratio [HR], 0.52 [95% confidence interval (CI), 0.30–0.92]; P = .02). The benefit of neoadjuvant chemotherapy varied significantly when stratified by tumor size. For tumors larger than 10 cm, the 3-year DSS was 62% for patients who underwent surgery alone and 83% for patients who received neoadjuvant chemotherapy (HR, 0.45 [95% CI, 0.2–0.83]). There was no difference in 3-year recurrence-free survival (RFS) between the surgery-alone and neoadjuvant chemotherapy groups (HR, 0.76 [95% CI, 0.51–1.1]; P = .19); however, there was a trend toward benefit to neoadjuvant chemotherapy in patients with tumors > 10 cm (HR, 0.62 [95% CI, 0.39–0.98]). Similarly, as most recurrences were distant recurrences, the 3-year freedom from distant recurrences was no different between the two groups; however, there again was a benefit to neoadjuvant chemotherapy in patients with tumors > 10 cm (HR, 0.67 [95% CI, 0.39–0.98]). This was the first study to demonstrate a potential benefit of neoadjuvant chemotherapy (21% survival benefit at 3 years) specifically in patients with tumors > 10 cm.

Radiographic response to neoadjuvant chemotherapy has been shown to predict improved local control and OS. Meric et al retrospectively reviewed the experience at MD Anderson Cancer Center in a group of 65 patients with grade 2/3, ≥ 5 cm, or locally recurrent extremity soft-tissue sarcomas.[12] Patients received either doxorubicin- or ifosfamide-based neoadjuvant chemotherapy. A partial response was observed in 22 patients (34%), a minor response in 6 patients (9%), stable disease in 20 patients (31%), and progressive disease in 17 patients (26%). Based on review of pre- and posttreatment imaging, 8 patients (13%) had downstaging of the scope of their operation, 50 patients (78%) had no change in their operative plan, and 6 patients (9%) had disease progression that increased the scope of their operation. All patients who were planned for a pretreatment amputation underwent amputation, and no patients with disease progression required an amputation when a limb-salvage operation was initially planned. OS was significantly longer in patients who demonstrated any radiographic response to neoadjuvant chemotherapy (HR, 6.6 [95% CI, 1.4–31.0]; P = .015). Additionally, patients who demonstrated a radiographic response were also found to have lower local recurrence rates compared with those who did not have a radiographic response (HR, 2.6 [95% CI, 1.0–6.8]; P = .04).

Radiation therapy

The role of RT is to decrease the risk of local recurrence. RT also has the potential to reduce tumor burden and improve limb-sparing R0 resection rates. However, wound complication rates can be high and associated with significant morbidity. Although neoadjuvant RT requires a smaller radiation field and leads to fewer long-term treatment-related complications such as fibrosis and joint immobility, it is associated with higher rates of short-term wound healing complications.

The use of neoadjuvant RT is supported by data from an RCT. In 2002, O’Sullivan et al conducted a multicenter phase III trial investigating the use of both neoadjuvant and adjuvant RT in patients with extremity soft-tissue sarcomas.[13] The primary endpoint in the study was the presence or absence of a wound complication, and secondary endpoints included local control, metastatic failure, progression-free survival (PFS), and OS. The patient group that underwent neoadjuvant RT included 88 patients who received 50 Gy (in 2-Gy fractions to a target volume of 5 cm) 3 to 6 weeks prior to surgery. Positive margins were observed in 14 patients (16%). With a median follow-up of 3.3 years, there was no difference in local recurrence rate, regional or distant failure rates, and PFS. OS was significantly improved in the neoadjuvant RT group (P = .048), although some of the deaths in the adjuvant therapy arm were from non-oncologic causes; oncologic-specific survival did not differ. Postoperative wound complications were significantly more common in the neoadjuvant RT group than in the adjuvant RT group (35% vs 17%; P = .01). However, follow-up analysis confirmed that patients undergoing postoperative adjuvant RT had worse long-term functional outcomes. Thus, the decision to select between neoadjuvant and adjuvant RT comes down to weighing the pros and cons of higher short-term, postoperative wound complications (neoadjuvant) vs worse posttreatment functional outcomes (adjuvant), with no clinically significant difference in PFS and OS.

In efforts to reduce postoperative wound complications associated with neoadjuvant RT, image-guided RT (IGRT) can be employed to limit the radiation exposure to normal surrounding tissue. By more precisely delineating the gross tumor volume using image guidance, the clinical target volume (ie, gross tumor volume with surrounding rim of normal tissue at risk for microscopic invasion) can be reduced, thus sparing normal tissue from potential late toxicities of radiation exposure. Recently, a phase II multi-institutional prospective trial was conducted (Radiation Therapy Oncology Group [RTOG] 0630 trial) to investigate the rate of late toxicities in patients with extremity soft-tissue sarcomas treated with IGRT.[14] A total of 98 patients with intermediate- to high-grade soft-tissue sarcomas ≥ 8 cm received RT plus chemotherapy (cohort A) or RT alone (cohort B). Cohort A closed early because of poor accrual and, as a result, analysis was limited to cohort B. Cohort B received 50 Gy in 25 fractions followed by surgery 4 to 8 weeks later. Only 11% of patients experienced grade 2 or higher late toxicity (subcutaneous tissue fibrosis, joint stiffness, or edema). Wound complications remained an issue, even with IGRT, as 26 patients (37%) experienced at least one wound complication, a quarter of whom required a secondary operative debridement. IGRT provided improved local control, with local recurrences occurring in only 2 of 56 patients with negative margins, with no marginal-field recurrences. Estimated 2-year local, regional, and distant treatment failure rates were 11%, 0%, and 37%, respectively, and the 2-year OS rate was 81%. These results illustrate the potential benefit of utilizing IGRT to achieve good local control rates with a favorable toxicity profile and the need for close monitoring for wound complications postoperatively.

Chemoradiation

Multiple studies have shown potentially favorable outcomes in patients with high-grade soft-tissue sarcomas who undergo treatment with neoadjuvant chemoradiation (Table). The toxicity of the chemotherapy regimens can be quite significant and must be weighed against the potential benefits of the treatment.

In 2003, DeLaney et al first reported results from a phase II study investigating outcomes in patients who received neoadjuvant chemotherapy interdigitated with RT for their high-grade soft-tissue sarcomas.[15] Patients with grade 2 or 3 tumors, ≥ 8 cm, were treated with 3 cycles of neoadjuvant mesna (2,500 mg/m²), adriamycin (20 mg/m²), ifosfamide (2 g/m²), and dacarbazine (250 mg/m²; MAID regimen) interdigitated with RT at a dose of 44 Gy followed by surgery 3 weeks after the completion of the protocol. Postoperatively, patients received an additional 16 Gy and 3 more cycles of MAID. Radiographic response was assessed in 47 of 48 patients who completed neoadjuvant treatment, of which 5 patients (11%) had a partial response, 36 patients (77%) had no response, and 6 patients (13%) had evidence of disease progression. All 48 patients underwent limb-sparing surgery, of which 7 (15%) had positive microscopic margins. There was no difference in the 5-year local control rate between the MAID group and a historical matched control group (92% vs 86%; P = .12). Freedom from distant metastases was significantly improved in the MAID group when compared with the control group (75% vs 47%; P = .002), in addition to DFS (70% vs 42%; P = .0002) and OS (87% vs 58%; P = .0003). Fourteen patients (29%) developed wound healing complications, of which nine patients required an operative intervention. These results initially provided support for a neoadjuvant regimen of chemotherapy interdigitated with RT in patients with high-risk extremity soft-tissue sarcomas.

The results from the phase II study by DeLaney et al[15] led to the RTOG 9514 multi-institutional phase II trial utilizing a similar protocol of neoadjuvant MAID chemotherapy with interdigitated RT.[16] This study focused on patients with high-risk, primary or locally recurrent, grade 2 or 3 extremity and torso soft-tissue sarcomas ≥ 8 cm. Fifty patients (79%) received all 3 cycles of neoadjuvant MAID, which included a higher dose of ifosfamide (2,500 mg/m²), and 56 patients (89%) received neoadjuvant RT per protocol.

Of 59 patients assessed for pathologic response, 38 (64%) had stable disease and 8 (14%) had progressive disease. Fourteen patients had no viable tumor on pathologic review of resection specimen. Sixty-one patients underwent surgery; 58 (91%) underwent an R0 resection, which included five amputations (92% limb-salvage rate). With a median follow-up of 33 months, 3-year DFS (57%), distant DFS (65%), and OS (75%) were consistent with the results reported by DeLaney et al. However, there was a greater rate of treatment toxicity, and fewer patients (59% vs 83%) were able to complete the modified MAID regimen, which has been attributed to the 25% greater dose of ifosfamide (2,500 mg/m² vs 2,000 mg/m²). Grade 3 or higher toxicities were observed in 97% of patients, including three deaths, two of which were secondary to acute myelogenous leukemia and the third from leukopenic sepsis.

Long-term results from the RTOG 9514 trial have since been reported.[17] Despite the considerably high rates of toxicity reported in the initial study, the risk of treatment toxicity was found to be short-term, since rates of toxicity decreased following the first year. At 1 and 2 years, the percentage of patients who experienced one or more grade 3 or 4 toxicities were 25% and 7%, respectively, with rates during years 3 to 5 reduced to 3% to 4%. At a median follow-up of 7.7 years, 35 patients (55%) were alive without evidence of disease. The 5-year locoregional failure rate was 22%, and the 5-year distant metastasis rate was 28%. The 5-year DFS, distant DFS, and OS were 56%, 64%, and 71%, respectively. Twenty-two deaths were reported, of which 15 were primary tumor–related, 3 treatment-related, 1 secondary to a second primary cancer, and 3 unknown. These results indicate that favorable long-term outcomes are attainable when utilizing neoadjuvant therapy; however, modifications are required to reduce the significant rate of early toxicities.

More recently, Mullen et al reported the long-term results of the DeLaney study[15] to further support the use of neoadjuvant chemoradiation.[18] Only five local failures were observed in the MAID group, for a local control rate of 90%. With a median follow-up of 7.6 years in the MAID group and 6.0 years in the historical matched control group, freedom from distant metastases and DFS at 10 years were significantly improved in the MAID group (77% vs 43%; P = .01 and 65% vs 30%; P = .0002, respectively). Additionally, the significantly higher 10-year DSS and OS in the MAID group (75% vs 47%; P = .004 and 66% vs 38%; P = .003, respectively) demonstrated the sustained survival benefit of neoadjuvant chemoradiation in patients with high-risk extremity soft-tissue sarcomas. Of the 48 patients in the MAID group, 16 deaths (33%; 11 sarcoma-related) were reported compared with 33 deaths (69%; 25 sarcoma-related) in the historical matched control group. However, it is challenging to know the significance of this approach in the absence of a phase III study, since comparison to historical matched controls is subject to subtle differences in other treatment variables.

These results have been further substantiated in a recent retrospective study by Look Hong et al,[19] in which the experience at the Massachusetts General Hospital was reviewed in the time from the completion of the initial study by DeLaney et al.[15] Sixty-six patients underwent neoadjuvant chemoradiation consisting of the MAID regimen with interdigitated RT, of which 83% of patients were able to complete the entire course. Of the 58 patients with imaging available to determine tumor response, 17 patients (29%) had a partial response, 36 patients (62%) had stable disease, and 5 patients (9%) had progressive disease. Twenty-one patients (32%) experienced a preoperative complication, of which 14 were chemotherapy-related and 2 radiation-related, and 5 patients experienced a venous thromboembolic event requiring preoperative anticoagulation. Postoperative wound complications were observed in 20 patients (30%). Locoregional recurrences occurred in 6 patients (9%) at a median of 33 months, and distant metastases were observed in 20 patients (30%) at a median of 10 months following diagnosis. At a median follow-up of 46 months, the 5-year locoregional and distant RFS rates were 91% and 64%, respectively. The 5-year DSS and OS rates were 86% and 89%, respectively. Only one treatment-related death from myelodysplasia was reported at 53 months after completion of chemotherapy.

The role of chemotherapy and RT for extremity and truncal soft-tissue sarcomas remains controversial. Based on the data available, it is generally our approach to routinely offer patients neoadjuvant RT, but not neoadjuvant chemotherapy. Neoadjuvant RT allows for a smaller radiation field than postoperative RT, limiting the extent of normal surrounding tissue exposed in order to preserve function. Although RT is associated with an increased incidence of postoperative wound complications, the potential for improved recurrence rates and survival outweigh this risk. This is in contrast to neoadjuvant chemotherapy, which is associated with significant treatment-related toxicities and unclear benefit.

Retroperitoneal Sarcomas

Sarcomas of the retroperitoneum present not only a unique challenge for surgical resection, but also for treatment in the neoadjuvant setting. Although limb and function preservation is a key concern in managing extremity soft-tissue sarcomas, surrounding organ injury prevention is paramount for retroperitoneal sarcomas. This is complicated by the common situation of multi-organ involvement by a tumor that is often in close proximity to vital structures. Accounting for only 15% of all soft-tissue sarcomas, the rarity of these sarcomas makes accruing patients into an RCT very difficult.[20] As a result, the lack of data from randomized prospective studies leads to ongoing uncertainty in optimal treatment strategies.

Chemotherapy

The role of chemotherapy in the treatment of retroperitoneal sarcomas is not well-defined. In the absence of consistent evidence of improved survival, the use of chemotherapy in patients with high-risk tumors or potentially aggressive histologies must be carefully weighed against the significant toxicities that are associated with these regimens. The optimal regimens have yet to be determined, and current regimens include doxorubicin-, dacarbazine-, or ifosfamide-based chemotherapy. The use of chemotherapy for retroperitoneal sarcomas is largely based on data extrapolated from extremity/trunk soft-tissue sarcomas, as well as from retrospective case series.

In a recent retrospective review from researchers at the University of Washington, Bremjit et al investigated the survival benefit in utilizing neoadjuvant chemotherapy in the treatment of retroperitoneal sarcomas.[21] Of 132 patients with primary retroperitoneal sarcomas, 28 (21%) received neoadjuvant chemotherapy. At the time of surgery, 8 patients had progressed (29%), 14 (50%) had stable disease, and 2 (7%) had responsive disease (response unknown in 4 patients). No survival benefit was observed in patients who received neoadjuvant chemotherapy; rather, there was a trend toward shorter OS in this cohort. These results are further supported by data from the National Cancer Data Base by Miura et al.[22] Of 8,653 patients included in the study, 163 (11%) received neoadjuvant chemotherapy. Neoadjuvant chemotherapy was found to be associated with worse median OS compared with surgery alone in a propensity-matched cohort (40 vs 52.4 months; P = .002).

Radiation therapy

The role of neoadjuvant RT in the management of retroperitoneal sarcomas has largely been investigated retrospectively due to the absence of data from RCTs. The use of RT in the treatment of retroperitoneal sarcomas is complex because of the irregular contours of the retroperitoneum, the typically large radiation field required, and the close proximity of vital radiosensitive structures. Neoadjuvant RT does have advantages over postoperative RT-the radiation field is more readily defined and radiosensitive structures (ie, small intestine/colon) have not filled the radiation field as they do after a tumor has been resected. A phase III trial to investigate the role of neoadjuvant RT was launched in 2004 by the American College of Surgeons Oncology Group (Z9031 trial); however, the trial was terminated due to poor accrual. Currently, a similarly designed international phase III trial (the EORTC 62092-22092 STRASS trial) is underway, investigating neoadjuvant RT plus surgery vs surgery alone in patients with primary retroperitoneal sarcomas.[23] Patients randomized to the investigational arm are to receive 50.4 Gy followed by surgery 4 to 8 weeks later. The primary outcome includes RFS, and secondary outcome measures include perioperative complication rates, tumor response to RT, metastasis-free survival, and OS. Trial accrual is projected to end in 2016 or 2017.

In the absence of data from randomized trials, the role of neoadjuvant RT in the management of retroperitoneal sarcomas has largely been based on multiple prior single-institution studies.[5,24,25] In 2006, Pawlik et al reported the largest series of outcomes by combining data from two prospective single-arm trials.[26-28] A total of 72 patients with intermediate- or high-grade tumors were included, of which 54 (75%) had primary disease. Of these patients, 75% received at least 45 Gy and 50% received doxorubicin concurrently with neoadjuvant RT (protocols differed between the two studies). Fifty-seven patients ultimately underwent resection with curative intent 4 to 8 weeks after the completion of RT. Of the 15 patients who did not undergo resection, 5 patients died (4 during RT, 1 in the post-radiation period) and 10 patients had disease progression and were deemed unresectable. A macroscopically complete resection (R0 or R1) was achieved in 54 patients (95%). Disease recurrence was observed at a median of 17.2 months in 28 patients (52%) who underwent R0/R1 resection. Recurrences included 17 patients (31%) with local failure, 8 (15%) with distant failure, and 3 (6%) with both local and distant failure. At a median follow-up of 40.3 months, the 2- and 5-year local RFS rates were 79% and 60%, respectively, and the 5-year OS was 61% for those patients who underwent an R0/R1 resection. These results demonstrated that neoadjuvant RT is feasible. Results were better than those in historical controls (with all of the caveats associated with such an analysis using historical controls). Local failures continued to be the predominant pattern of recurrence, despite a 5-year local RFS rate of 60%.

Most recently, Nussbaum et al used data from the National Cancer Data Base to evaluate long-term outcomes associated with neoadjuvant RT for retroperitoneal sarcomas.[29] Out of a total of 11,324 patients who underwent resection, 696 (6%) received neoadjuvant RT. No significant benefit in 5-year OS was observed in patients who received neoadjuvant RT when using propensity-matched groups (53% vs 54%; P = .695). However, when looking only at high-grade tumors (moderate, poor, and undifferentiated histology), neoadjuvant RT was associated with a statistically significant 5-year OS benefit (49% vs 46%; P = .022). Caution must be used when interpreting these results due to selection bias that is inherent to retrospective database studies. It is important to note that 27% of the patients who did not receive neoadjuvant RT went on to receive postoperative RT, compared with 6% of those who received neoadjuvant radiation. This crossover could potentially mask an even greater benefit from just neoadjuvant RT alone. This study further emphasizes the need for level I evidence, which will hopefully come from the ongoing EORTC trial.

It is our general practice to offer enrollment in the EORTC phase III study if a patient agrees to randomization; otherwise, we utilize neoadjuvant RT. We typically reserve neoadjuvant chemotherapy for borderline resectable or locally advanced presentations of primary retroperitoneal sarcomas, such as those arising from the inferior vena cava with partial aortic encasement. Similar to extremity soft-tissue sarcomas, RT in the neoadjuvant setting allows for a limited field that reduces potential damage to surrounding normal tissue. The postoperative radiation field includes the tumor bed, which typically becomes filled with surrounding small intestine or colon, thus increasing the exposure of radiation to normal structures. Therefore, we do not endorse the use of postoperative RT in such patients.[30] In the absence of convincing data to support the use of neoadjuvant chemotherapy, we do not consider its use in our patients. Until the results of the EORTC trial are reported, practice patterns will continue to exhibit significant variability.[31]

Conclusion

Soft-tissue sarcomas provide clinicians with a unique challenge because of the anatomical complexities involved and limited level I evidence available to guide management strategies. Their rarity and histologic heterogeneity make conducting large, prospective, randomized trials very difficult. As a result, there is considerable variability in practice patterns. Optimal management of soft-tissue sarcomas requires a multidisciplinary approach at a specialized sarcoma center. In general, it is our practice to avoid the use of neoadjuvant chemotherapy for extremity/trunk and retroperitoneal sarcomas due to lack of evidence demonstrating a survival benefit, as well as the associated significant toxicities. Although neoadjuvant RT is associated with an increased incidence of postoperative wound complications, the limited radiation field required for neoadjuvant treatment reduces the toxicity to adjacent structures, and in extremity soft-tissue sarcomas, is associated with better functional outcomes than postoperative RT. These patients do require close postoperative monitoring for prompt recognition of potential wound complications. As more prospective, multi-institutional studies are initiated, and the highly anticipated results of the EORTC trial are reported, the care of patients with soft-tissue sarcomas will continue to be optimized.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29.

2. Gronchi A, Lo Vullo S, Fiore M, et al. Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol. 2009;27:24-30.

3. Bonvalot S, Miceli R, Berselli M, et al. Aggressive surgery in retroperitoneal soft tissue sarcoma carried out at high-volume centers is safe and is associated with improved local control. Ann Surg Oncol. 2010;17:1507-14.

4. Gronchi A, Miceli R, Shurell E, et al. Outcome prediction in primary resected retroperitoneal soft tissue sarcoma: histology-specific overall survival and disease-free survival nomograms built on major sarcoma center data sets. J Clin Oncol. 2013;31:1649-55.

5. McBride SM, Raut CP, Lapidus M, et al. Locoregional recurrence after preoperative radiation therapy for retroperitoneal sarcoma: adverse impact of multifocal disease and potential implications of dose escalation. Ann Surg Oncol. 2013;20:2140-7.

6. Keung EZ, Hornick JL, Bertagnolli MM, et al. Predictors of outcomes in patients with primary retroperitoneal dedifferentiated liposarcoma undergoing surgery. J Am Coll Surg. 2014;218:206-17.

7. Brennan MF. Lessons learned from the study of soft tissue sarcoma. Int J Surg. 2013;11(suppl 1):S8-S10.

8. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg. 1982;196:305-15.

9. Spiro IJ, Gebhardt MC, Jennings LC, et al. Prognostic factors for local control of sarcomas of the soft tissues managed by radiation and surgery. Semin Oncol. 1997;24:540-6.

10. Gortzak E, Azzarelli A, Buesa J, et al. A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer. 2001;37:1096-103.

11. Grobmyer SR, Maki RG, Demetri GD, et al. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15:1667-72.

12. Meric F, Hess KR, Varma DG, et al. Radiographic response to neoadjuvant chemotherapy is a predictor of local control and survival in soft tissue sarcomas. Cancer. 2002;95:1120-6.

13. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235-41.

14. Wang D, Zhang Q, Eisenberg BL, et al. Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: results of Radiation Therapy Oncology Group RTOG-0630 trial. J Clin Oncol. 2015;33:2231-8.

15. DeLaney TF, Spiro IJ, Suit HD, et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. 2003;56:1117-27.

16. Kraybill WG, Harris J, Spiro IJ, et al. 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: Radiation Therapy Oncology Group trial 9514. J Clin Oncol. 2006;24:619-25.

17. Kraybill WG, Harris J, Spiro IJ, et al. Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group trial 9514. Cancer. 2010;116:4613-21.

18. Mullen JT, Kobayashi W, Wang JJ, et al. Long-term follow-up of patients treated with neoadjuvant chemotherapy and radiotherapy for large, extremity soft tissue sarcomas. Cancer. 2012;118:3758-65.

19. Look Hong NJ, Hornicek FJ, Harmon DC, et al. Neoadjuvant chemoradiotherapy for patients with high-risk extremity and truncal sarcomas: a 10-year single institution retrospective study. Eur J Cancer. 2013;49:875-83.

20. Strauss DC, Hayes AJ, Thway K, et al. Surgical management of primary retroperitoneal sarcoma. Br J Surg. 2010;97:698-706.

21. Bremjit PJ, Jones RL, Chai X, et al. A contemporary large single-institution evaluation of resected retroperitoneal sarcoma. Ann Surg Oncol. 2014;21:2150-8.

22. Miura JT, Charlson J, Gamblin TC, et al. Impact of chemotherapy on survival in surgically resected retroperitoneal sarcoma. Eur J Surg Oncol. 2015;41:1386-92.

23. European Organisation for the Research and Treatment of Cancer. A phase III randomized study of preoperative radiotherapy plus surgery versus surgery alone for patients with retroperitoneal sarcomas (RPS)-STRASS. http://www.eortc.be/clinicaltrials/details.asp?protocol=62092. Accessed January 4, 2016.

24. Caudle AS, Tepper JE, Calvo BF, et al. Complications associated with neoadjuvant radiotherapy in the multidisciplinary treatment of retroperitoneal sarcomas. Ann Surg Oncol. 2007;14:577-82.

25. El-Bared N, Taussky D, Mehiri S, et al. Preoperative intensity modulated radiation therapy for retroperitoneal sarcoma. Technol Cancer Res Treat. 2014;13:211-6.

26. Pisters PW, Ballo MT, Fenstermacher MJ, et al. Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol. 2003;21:3092-7.

27. Jones JJ, Catton CN, O’Sullivan B, et al. Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol. 2002;9:346-54.

28. Pawlik TM, Pisters PW, Mikula L, et al. Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol. 2006;13:508-17.

29. Nussbaum DP, Speicher PJ, Gulack BC, et al. Long-term oncologic outcomes after neoadjuvant radiation therapy for retroperitoneal sarcomas. Ann Surg. 2015;262:163-70.

30. Trans-Atlantic RPS Working Group. Management of primary retroperitoneal sarcoma (RPS) in the adult: a consensus approach from the Trans-Atlantic RPS Working Group. Ann Surg Oncol. 2015;22:256-63.

31. Gronchi A, Strauss D, Miceli R, et al. Malignancy Grade and Histologic Subtype of Primary Retroperioneal Sarcoma (RPS) Are Predictive of Pattern of Recurrence: A Large Retrospective Study from the Transatlantic RPS Working Group. Presented at the Connective Tissue Oncology Society Annual Meeting; October 15-18, 2014; Berlin, Germany.