Adjuvant Chemotherapy for Soft Tissue Sarcomas

Soft tissue sarcomas are rare mesenchymal neoplasms with considerable heterogeneity in biologic behavior and response to systemic therapy. Most patients present with localized disease and are potentially curable with multidisciplinary treatment. In patients with a high risk of developing metastatic disease, optimal use of neoadjuvant/adjuvant therapy has a definite role in improving patient outcomes by decreasing local and distant recurrences. Histology-specific clinical trials enrolling a homogenous high-risk population have been more successful in demonstrating benefit than larger trials with unselected heterogeneous patient populations. In specific histologic subtypes responsive to chemotherapy, neoadjuvant chemotherapy with close monitoring of response is recommended.

Soft tissue sarcomas (STS) are mesenchymal neoplasms arising from the connective tissue in the body. There is considerable heterogeneity among STS with more than 50 distinct histologic subtypes. Each of these histologic subtypes represents a unique disease with distinct biologic behavior and varying sensitivity to chemotherapy. Approximately 54% of STS are localized at diagnosis, representing a potentially curable subpopulation. Four thousand patients die of STS every year, mostly from distant metastatic disease. The judicious use of adjuvant/neoadjuvant chemotherapy along with surgery and radiation in the treatment of localized STS has a role in improving patient outcomes by decreasing local and distant recurrences.

The use of adjuvant chemotherapy in an unselected population results in limited benefit. In the authors’ opinion, it is important to identify the subpopulation that is most likely to die of metastatic disease. The application of effective therapies in this subset will result in the most benefit. There are 2 prerequisites to effective adjuvant therapy: (1) the identification of patients who are high risk for developing fatal metastatic disease and (2) the availability of effective histology-specific treatment options. For example, adjuvant therapy for rhabdomyosarcoma, a biologically aggressive histologic subtype with high metastatic potential, using effective treatment regimens results in significant clinical benefit. A primary tumor size greater than 5 cm, high grade, tumor involving or deep to the fascia, specific histologic subtypes ( Table 1 ), and recurrent disease are all associated with a higher likelihood of developing metastatic disease.

Table 1

The metastatic potential for various histologic subtypes of soft tissue sarcoma

Low Metastatic Potential	Intermediate Metastatic Potential	High Metastatic Potential
Well-differentiated liposarcoma	Inflammatory myofibroblastic tumor	Pleomorphic liposarcoma
	Epithelioid hemangioendothelioma	Dedifferentiated liposarcoma
	Solitary fibrous tumor Hemangiopericytoma	Leiomyosarcoma
		Round cell liposarcoma
		Malignant fibrous histiocytoma
		Angiosarcoma
		Rhabdomyosarcoma
		Synovial sarcoma
		Extraskeletal Ewing sarcoma
		Epithelioid sarcoma
		Alveolar soft parts sarcoma
		Gastrointestinal stromal tumor

Most patients with distant relapse tend to die of their disease, so early incorporation of adjuvant chemotherapy in the multidisciplinary treatment to eradicate micrometastases is important. Combination regimens used extensively in the treatment of STS include (1) Adriamycin/ifosfamide, (2) Adriamycin/dacarbazine, and (3) gemcitabine/docetaxel. However, the sensitivity of various subtypes to these combinations is different and should be taken into account. For example, some STS, such as alveolar soft part sarcoma (ASPS), have a high propensity for metastases but with minimally effective systemic therapy options. Consequently, ASPS should be treated with local therapy; adjuvant systemic therapy should be avoided outside of a clinical trial.

Adjuvant systemic chemotherapy for STS

Prospective Studies of Adriamycin

Adriamycin was introduced as an active agent for advanced STS in the 1970s. One of the earliest randomized clinical trials examining the role of adjuvant chemotherapy was done at the National Cancer Institute where Dr Rosenberg and colleagues randomized 65 patients with high-grade extremity STS to receive either adjuvant Adriamycin, cyclophosphamide, and methotrexate or no chemotherapy. They were able to demonstrate improved disease-free survival (DFS) and overall survival (OS) in the adjuvant chemotherapy group (3 years DFS 92% vs 60%, OS 95% vs 74%). There was no local recurrence (LR) in the adjuvant therapy group as compared with 2 LR in the no chemotherapy group. Interestingly, synovial sarcoma and rhabdomyosarcoma, 2 histologic subtypes with aggressive biologic behavior, were disproportionately more prevalent in the adjuvant therapy group. This imbalance did not adversely affect the outcome of the chemotherapy group, supporting the hypothesis that the benefit of adjuvant chemotherapy is best demonstrated in aggressive STS subtypes.

Similarly, Gherlinzoni and colleagues randomized 59 high-grade STS to receive either Adriamycin 450 mg/m ²or no adjuvant therapy after surgery and radiation. DFS in the adjuvant chemotherapy group was 79.1% versus 54.3% in the no chemotherapy group. Development of pulmonary metastases was much more frequent in the no chemotherapy group (40%) as compared with the adjuvant chemotherapy group (16.6%). LR was also more common in the no chemotherapy group (8.6% vs 4.1%).

Antman and colleagues randomized 42 patients to receive 5 cycles of adjuvant Adriamycin 90 mg/m ²every 3 weeks versus observation. The largest histologic subtype enrolled was liposarcoma (40% in the treatment group and 32% in the observation group), but this histology was not further subclassified into well-differentiated, dedifferentiated, pleomorphic, or myxoid subtypes. Besides liposarcoma, the trial enrolled 9 other histologic types of STS. The authors reported a 12% improvement in DFS and an 8% improvement in OS for adjuvant chemotherapy. However, this failed to achieve statistical significance because of the small sample size.

Prospective Studies of Adriamycin and Ifosfamide

Brodowicz and colleagues randomized 59 patients to receive 6 courses of adjuvant Adriamycin (50 mg/m ²per cycle), ifosfamide (6 g/m ²per cycle), and dacarbazine (800 mg/m ²per cycle) versus observation after the resection of localized STS. Grade 3 tumors were present in 81% of patients in the chemotherapy arm and 57% of patients in the control arm. Despite higher preponderance of high grade within the chemotherapy arm, 77% of patients in this group were recurrence free versus 57% of patients in the control arm (mean follow-up 41 months). The relapse-free survival, time to local failure, time to distant failure, and OS were not significantly different between the 2 treatment groups, likely because of the small sample size and short follow-up.

Frustaci and colleagues randomized 104 patients with high-grade extremity STS greater than or equal to 5 cm to receive 5 cycles of epirubicin (120 mg/m ²per cycle) and ifosfamide (9 g/m ²per cycle) or observation after local therapy. At a median follow-up of 59 months, median DFS was 48 months in the treatment group versus 16 months in the control group. The median OS was 75 months for the treatment group as compared with 46 months for the control group. For OS, the absolute benefit from chemotherapy was 13% at 2 years and increased to 19% at 4 years ( Table 2 ). The authors published follow-up data 2 years later showing a 5-year OS of 66% versus 46% favoring adjuvant therapy ( P = .04). However, longer follow-up after 89.6 months showed that the difference favoring adjuvant therapy lost statistical significance ( P = .07).

Table 2

Clinical trials examining the role of adjuvant chemotherapy for soft tissue sarcomas

Year	Author	Patients	Histologic Subtypes ^a	High Grade (%)	Site	Regimen/Dose	Measure	Outcome Rx (%)	Control (%)	Statistical Significance
1983	Rosenberg et al	65	MFH Synovial sarcoma Liposarcoma	78	E	ADM 50–70 mg/m ²^b CTX 500–700 mg/m ² MTX 50–250 mg/kg ^c	DFS at 3 y OS LR	92 95 0	60 74 7	S S
1984	Antman et al	42	Liposarcoma mixed ^d	74	E, T	ADM 90 mg/m ²	DFS OS	80 85	68 77	NS NS
1986	Gherlinzoni et al	59	MFH Synovial sarcoma Fibrosarcoma	100	E	ADM 450 mg/m ² (cumulative)	DFS Lung mets LR	79 17 4	54 40 9	S
2000	Brodowicz et al	59	Liposarcoma MFH Synovial sarcoma	69	E, T	ADM 50 mg/m ² IF 6 g/m ² DTIC 800 mg/m ²	DFS LR DR	77 6 19	57 21 36	NS NS NS
2001	Frustaci et al	104	MFH Synovial sarcoma Liposarcoma	100	E	EPI 120 mg/m ² IF 9 g/m ²	DFS 2 y DFS 4 y LR 2 y ^e LR 4 y ^e DR 2 y ^e DR 4 y ^e OS 2 y OS 4 y	72 50 0 6 28 44 85 69	45 37 10 17 45 45 72 50	S NS S NS NS NS NS S
2002	Petrioli et al	88	MFH Liposarcoma Leiomyosarcoma	41	E, T	EPI 75 mg/m ² IF 6 g/m ²	DFS 5 y OS 5 y	69 72	44 47	S NS
2007 ^f	Woll PJ et al	351	Leiomyosarcoma Liposarcoma MFH Synovial sarcoma ^g	60	E, T	ADM 75 mg/m ² IF 5 g/m ²	DFS 5 y OS	52 64	52 69	NS NS