Soft tissue sarcomas (STSs) are rare neoplasms and account for 1% of all solid tumors in adults. In 2013, there were 11,410 new cases diagnosed in adults and children in the United States, with 4390 expected deaths [1]. There are no data on such estimates in Brazil. By inference, using the American population, we have predicted an annual incidence of 7060 cases for 2013.

Approximately 50% to 60% of cases develop in the limbs, which can differentiate into more than 50 histological subtypes [2]. High-grade sarcomas, which are deep and larger than 5 cm, are locally aggressive and cause distant metastases, primarily to the lungs. The risk of lung metastasis from high-grade tumors ranges from 34% in 5- to 10-cm lesions to 43% for those over 10 cm [3].

The treatment for STSs, which are localized but not amenable to adequate resection, is multimodal in most cases and often involves surgery, chemotherapy, and radiotherapy (RT) [3]. Nevertheless, selecting patients to receive chemotherapy as adjuvant treatment is an option to avoid unnecessary toxic treatment in cases that are considered to be nonresponsive; this approach increases the rates of limb sparing but fails to improve overall survival (OS)—patients continue to die of metastatic disease, especially in the lung. Further, choosing an RT scheme that reduces wound complication rates might increase the number of patients who receive chemotherapy when it is indicated.

To increase the tumor necrosis rate in patients with STSs of the extremities that are not amenable to adequate resection, with regard to their survival, we have proposed a treatment regimen in which neoadjuvant chemotherapy is administered with concomitant hypofractionated RT and adjuvant chemotherapy for select cases, depending on the viable cell count. Our aim is to maintain morbidity and mortality rates compared with the current regimen, improve survival, and spare patients who are considered to be poor responders from unnecessary chemotherapy.

Patients have been recruited since February 2015, and recruitment is expected to be finished by the end of 2018. We are trying to change this protocol to a multicenter study in order to have 70 patients, based on the sample size calculation.

After the enrollment of the first 20 patients, an interim analysis is planned that focuses on side effects. The follow-up period will be at least 3 years after treatment, and it will include metastatic patients depending on the early results.

The main hypothesis is that the addition of hypofractionated RT can increase the necrosis rate, and we expect to have a higher rate of complete pathological response than in our previous 16% (data not shown), that was achieved using only chemotherapy. Whether this mechanism is related to survival remains unclear.

The prognosis of patients with high-grade STS remains poor, primarily due to relapses at distant sites [3]. Because STSs are rare, cases in most studies are separated into high-grade and low-grade tumors. This classification guides the therapy in most patients, although other factors such as tumor size and depth also correlate with relapse and death [1]. Tumor severity is another predictor of the response to cytotoxic therapies, wherein better response rates are observed with high-grade tumors. Thus, chemotherapy remains warranted for patients with high-grade tumors, irrespective of histological type, although some of them might respond differently to specific drugs [10,11].

Neoadjuvant chemotherapy,despite being a nonstandard treatment, can theoretically facilitate tumor resection with adequate margins and combat micrometastatic disease early and allow in vivo verification of the clinical or pathological response to chemotherapy after surgery. The pathological response that is induced by the treatment and the subsequent effects on survival have been the subjects of many studies [12-14], such as Gomez et al [15]. This group performed a retrospective study of patients with extremity high-grade sarcomas who underwent neoadjuvant treatment with RT and chemotherapy. Local disease-free survival and OS were significantly better in patients who exhibited more than 95% necrosis in the surgical specimen. The addition of ifosfamide to the regimen increased the percentage of patients with ≥95% necrosis from 13% to 48%, improving survival rates [16].

We used the standardized RECIST criteria [5] to evaluate the clinical response to preoperative treatment. The main limitation of this method is that it is one-dimensional with respect to the assessment of the primary lesion, because shrinkage of the tumor might be absent, but we believe that it is simple to implement and interpret. Consequently, the RECIST criteria remain widely used in measuring the clinical response to treatment for solid tumors [17].

Our previous results showed a wound complication rate (rWC) of nearly 42% using conventional chemotherapy/RT preoperatively, indicating that approximately 70% of patients failed to receive or were delayed in receiving adjuvant chemotherapy. Thus, in 2005, we began a new prospective phase 2 study using preoperative chemotherapy and relegating RT to the adjuvant scenario to reduce the surgical rWC. It was imperative to evaluate whether this preoperative chemotherapy regimen lowered the rWC without altering local control or amputation rates. Our group proposed that the action of systemic chemotherapy and its effect on the tumor, as a neoadjuvant treatment, be examined measuring the pathological response based on the quantification of necrosis, fibrosis, and the percentage of viable cells in surgical specimens.

From April 2005 to July 2012, 48 patients with high-grade extremity STSs were assessed; the median follow-up time was 40 months. The OS rates for nonmetastatic patients were 86.3% and 74.1% at 3 and 5 years, respectively, with an rWC of 19.5%. The analysis of surgical specimens showed that 6 patients (15%) had 5% (or less) viable cells in the sample, for whom the estimated OS and relapse-free survival (RFS) at 5 years were 100%. With a cutoff of 30% or less, 15 patients (37.5%) had an RFS of 82% and an OS of 90.9%.

Despite the favorable results with regard to avoiding the conventional preoperative RT scheme, the use of neoadjuvant chemotherapy alone has not effected better outcomes and subjects patients to higher doses due to larger fields of radiation postoperatively, correlating with late functional complications such as fibrosis and joint limitations. A different RT modality might solve or minimize this problem.

Hypofractionated treatment has comparable efficacy and safety as conventional fractionation in other solid tumors, such as those of the breast, prostate, and rectum. The usual dose for neoadjuvant RT in sarcomas is 50 Gy/25 fractions of 2 Gy. Radiobiology studies have shown that the sarcoma alpha/beta relationship is less than 10 Gy, which favors hypofractionated treatment [18]. Despite chemotherapy sometime being used concomitantly with RT, there is no standard treatment for hypofractionated RT. Ryan et al [19] prospectively treated 25 patients with hypofractionated RT (28 Gy/8 fractions) concomitant with chemotherapy with epirubicin and ifosfamide (3 cycles each pre- and postoperatively). This group reported high rates of hematological toxicity, with 64% of patients completing all chemotherapy cycles. Overall and disease-free survival was 84% and 62%, respectively.

More recently, a prospective study reported the results on 272 patients who were treated with an RT regimen that was similar to that in our study, with 25 Gy/5 fractions followed by immediate surgery (3 to 7 days after the end of RT) [20]. Some patients (22%) also underwent neoadjuvant chemotherapy. The OS rate at 3 years was 72%, with 42% of patients experiencing some acute toxicity and 7% requiring surgical intervention. The authors concluded that hypofractionated treatment generates similar results in terms of local control and OS compared with conventional treatment, with acceptable toxicity.

A criticism of chemotherapy for sarcomas is that histological types respond differently to several types of drugs. According to a multivariate analysis by the Italian and Spanish Sarcoma Group [21], histological subtype was associated with a difference in survival after chemotherapy, and patients with leiomyosarcoma had the worst prognosis. However, most studies claim that chemotherapy with doxorubicin must be maintained for most tumors of this type [22].

In this study, we added chemotherapy preoperatively to combat micrometastatic disease early and identify patients who were good responders (ie, harboring fewer than 30% viable cells in surgical specimens). For these responders who have received chemotherapy and hypofractionated RT, we offer 3 additional cycles of chemotherapy as an adjuvant treatment, avoiding chemotherapy for patients who theoretically do not need it.

Our main concerns are related to recruitment issues. Because STS is a rare condition, attaining the calculated sample size will be difficult. Most patients with high-grade STS are metastatic at the diagnosis, which is an exclusion criterion. However, as a cancer center, our institution receives patients from throughout Brazil, despite the lack of a specific government program.

Hypofractionated RT plus adjuvant chemotherapy can increase the pathological response and improve the outcomes of select patients, avoiding unnecessary chemotherapy and instead offering more chemotherapy to good responders. This approach is a rational use of adjuvant chemotherapy, despite the many histological types of sarcoma and limited chemotherapy schemes for sarcomas. We are confident that adding hypofractionated RT in the neoadjuvant scenario can shorten treatment times and lower costs without increasing the rWC compared with conventional RT.