Soft-Tissue Sarcomas

Role of Adjuvant Chemotherapy

The striking success of combined-modality therapy in children with osteogenic sarcoma, rhabdomyosarcoma, and the Ewing sarcoma family of tumors has provided the stimulus for the use of aggressive combined-modality approaches in adults. The literature is replete with reports of the apparent benefit of combined-modality therapy in patients with resectable soft-tissue sarcoma, yet most series are either retrospective or small nonrandomized trials.

Preoperative chemotherapy

Preoperative chemotherapy has been adopted at many centers for patients with large high-grade sarcoma. The specific regimens employed have evolved over the years but generally contain both an anthracycline and ifosfamide(Drug information on ifosfamide).

Aside from theoretic considerations, there are several pragmatic reasons to favor preoperative over postoperative treatment. First, a reduction in the size of a large lesion may permit surgical resection with less morbidity. Second, compliance may be better with preoperative therapy. One observation that supports the neoadjuvant approach is that response to preoperative chemotherapy, whether pathologic or radiographic, predicts improved tumor control and survival.

Neoadjuvant chemotherapy has been explored in a prospective randomized trial initiated by the EORTC. The trial was open to patients who had a sarcoma measuring at least 8 cm (of any grade), a primary or recurrent intermediate- to high-grade sarcoma of any size, or a locally recurrent or inadequately excised grade 2-3 of 3 sarcoma. In spite of these broad eligibility criteria, accrual was slow, and the trial was closed after only 150 patients entered.

Patients were randomized to receive either immediate surgery, followed by radiation therapy for close or positive margins, or 3 cycles of chemotherapy with doxorubicin(Drug information on doxorubicin) (50 mg/m² by IV bolus) plus ifosfamide (5 g/m² by 24-hour continuous infusion) with mesna(Drug information on mesna) (Mesnex). Among the 134 eligible patients, over 80% had primary tumors of the extremities, but only 4% had grade 2 or 3 lesions > 8 cm. Among 49 patients evaluable for response, 29% had major objective responses, including four complete responses. Only 18% had progression of disease before surgery. Chemotherapy was generally well tolerated and never prevented surgery. With a median follow-up of 7.3 years, the estimated 5-year survival rate was similar for both groups.

Trials have explored the role of neoadjuvant chemotherapy and radiation therapy to decrease the rate of distant failure and possibly impact survival. A study reported from Massachusetts General Hospital enrolled patients with high-grade soft- tissue sarcomas (8 cm or larger). Patients were treated with 3 cycles of preoperative chemotherapy consisting of MAID (mesna, doxorubicin [Adriamycin], ifosfamide, dacarbazine(Drug information on dacarbazine)) interdigitated with 44 Gy of radiation therapy. This regimen was followed by surgical resection and 3 cycles of postoperative MAID chemotherapy. In cases with positive surgical margins, an additional 16 Gy of radiation therapy was delivered. This regimen resulted in a significant improvement in 5-year freedom from distant metastasis (75% vs 44%; P = .0016) when compared with historic control patients. Additionally, 5-year disease-free and overall survival rates were 70% vs 42% P = .0002) and 87% vs 58% (P = .0003) for the MAID and control groups, respectively. There was a 29% rate of wound healing complications in the MAID group.

These data have been extended in a follow-up study of similar interdigitated chemotherapy/radiation therapy in a phase II study from the Radiation Therapy Oncology Group (RTOG). In this study, 66 patients with primary high-grade soft-tissue sarcoma ≥ 8 cm in diameter received a modified MAID regimen plus granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim) [Neupogen]) and radiation therapy, followed by resection and postoperative chemotherapy. Preoperative radiotherapy and chemotherapy were successfully completed by 89% and 79% of patients, respectively. Grade 4 hematologic and nonhematologic toxicities affected 80% and 23% of patients, respectively. Two patients developed acute myelogenous leukemia (AML) following therapy. Delayed wound healing was noted in 31%. The estimated 3-year survival, disease-free survival, and local tumor control rates were 75%, 55%, and 79%, respectively.

The MD Anderson Cancer Center conducted a phase I trial to define the maximum tolerated dose of continuous-infusion doxorubicin administered with preoperative radiation therapy to a dose of 50 Gy. In total, 27 patients with intermediate- or high-grade sarcomas were enrolled in the trial. The maximum tolerated dose of doxorubicin was 17.5 mg/m²/week. Twenty-six patients underwent surgery, and all had a macroscopic complete resection (R0 or R1). Two patients had a pathologic complete response. These studies suggest that further investigation of a preoperative approach combining chemotherapy and radiation therapy is warranted. The lack of randomized data regarding the addition of chemotherapy to radiation therapy for extremity sarcomas limits the ability to apply these treatment regimens outside the setting of a study.

Postoperative chemotherapy

A number of published trials have compared postoperative chemotherapy with observation alone in adults who had undergone resection of a primary or recurrent soft-tissue sarcoma. Most of these trials included fewer than 100 patients, and even the largest trial had inadequate statistical power to detect a 15% difference in survival. Other flaws confound the interpretation of many of the studies. Some trials included low-risk patients with small and/or low-grade sarcomas. In some trials, patient ineligibility rates were as high as 20%, and in none of the trials published before 2000 was ifosfamide part of the combination evaluated.

In five of the six trials in which doxorubicin monotherapy was studied, including one study limited to patients with uterine sarcoma, a significant improvement in survival could not be demonstrated. Among the trials of combination chemotherapy, most used the combination known as CyVADIC (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dacarbazine). A significant survival advantage was seen in only one combination chemotherapy trial.

Nonetheless, some of the trials showed a trend or a statistically significant improvement in disease-free survival among patients who were administered adjuvant chemotherapy, especially among those with high-grade sarcomas of the extremities. Analyses of the pooled results of the published literature are consistent with this observation.

Ifosfamide-containing trials. Only one trial included in a meta-analysis by the Sarcoma Meta-Analysis Collaboration (SMAC) used an ifosfamide-containing regimen; that trial involved only 29 patients. An attempt to conduct a large prospective trial of postoperative chemotherapy with the MAID regimen in the United States failed because of insufficient patient accrual.

An Italian cooperative group conducted a trial in which patients 18 to 65 years old with high-grade (> 5 cm) or any recurrent sarcoma of the extremities were randomized to receive postoperative chemotherapy or observation alone. The treatment consisted of 5 cycles of epirubicin(Drug information on epirubicin) at 60 mg/m² on days 1 and 2, plus ifosfamide at 1.8 g/m² on days 1 to 5. Filgrastim was used to support the granulocyte counts during therapy.

The trial had been planned to accrue 200 patients but was interrupted after accrual of 104 patients, when an interim analysis showed a significant survival advantage for the chemotherapy-treated group. At 36 months after the last randomization, with a median follow-up of 59 months, median overall survival among the patients who received adjuvant chemotherapy was 75 months, vs 46 months for control patients (P = .03). In a longer-term follow-up analysis, survival was not improved in an intention-to-treat analysis, although 5-year overall survival rates still favored the patients receiving chemotherapy.

An analysis of adjuvant chemotherapy using doxorubicin and ifosfamide was conducted by the EORTC. This study examined surgery and adjuvant radiation therapy vs the same local therapy and adjuvant chemotherapy with 5 cycles of doxorubicin (75 mg/m²) and ifosfamide (5 g/m²) every 21 days. The data indicated no benefit in overall survival for the chemotherapy arm and tempered some of the enthusiasm regarding adjuvant chemotherapy as demonstrated in a positive Italian study of epirubicin and ifosfamide.

Since the time of the original Italian study, two other randomized studies have been performed. They do not indicate a benefit for chemotherapy but were underpowered to detect small differences in outcome.

Sarcoma Meta-Analysis Collaboration (SMAC) and newer meta-analyses. A formal meta-analysis of individual data from 1,568 patients who participated in randomized trials of postoperative adjuvant chemotherapy vs no chemotherapy control patients was performed by the SMAC and published in 1997. Although not all data were available for all patients, the analysis demonstrated a significant reduction in the risk of local or distant recurrence in patients who received adjuvant chemotherapy.

The overall hazard ratio (HR) for distant relapse-free survival was 0.70. The absolute benefit at 10 years was 10%, improving the recurrence-free survival rate at 10 years from 60% to 70%. Also, the HR for local recurrence-free survival was 0.73 (27% reduction in the risk of local recurrence), and the absolute benefit was 6%.

The HR for overall survival, however, was 0.89, which did not meet the criteria for statistical significance. The observed survival at 10 years was 54% for patients who received chemotherapy and 50% for those who did not. Subset analysis failed to show that the effects of chemotherapy differed by primary site, although the best evidence for an effect of adjuvant chemotherapy was seen in patients with sarcoma of the extremities.

A newer meta-analysis, including more ifosfamide-based studies, although excluding the large randomized EORTC 62931 study, confirms the trend seen in the SMAC meta-analysis, with an overall survival benefit of adjuvant chemotherapy. In this updated meta-analysis, 18 trials, representing 1,953 patients, were examined. The odds ratio (OR) for local recurrence was 0.73 in favor of chemotherapy (P = .02). In terms of overall survival, use of doxorubicin-based therapy without ifosfamide had an OR of 0.84, which was not statistically significant (P = .09). However, the OR for doxorubicin/ifosfamide-based therapy was 0.56 (P = .01) in favor of chemotherapy. The updated meta-analysis confirmed the SMAC meta-analysis in that there was efficacy of adjuvant chemotherapy for resected soft-tissue sarcoma with respect to local recurrence, distant recurrence, overall recurrence, and overall survival. The authors concluded that benefits were further improved with the addition of ifosfamide to doxorubicin-based regimens but must be weighed against the toxicity of the addition of ifosfamide.

Analyses of other collected prospective data regarding adjuvant chemotherapy from large referral centers have yielded conflicting data. In two analyses of patients with synovial sarcoma and one involving myxoid/round cell liposarcoma, chemotherapy appeared to improve overall survival. In a large analysis of two prospective databases, patients receiving chemotherapy initially had superior survival but then suffered inferior survival compared with those who received no adjuvant chemotherapy. Notably, patients were not randomized as part of their treatment. Given the fact that this was a registry instead of a randomized study, there was by definition a bias to treat patients who had higher-risk tumors with chemotherapy, although this did not appear to correlate with a specific single variable in the analysis. The data from the most recent meta-analysis appear to be consistent with data from prior studies when taken as a whole. If there is a benefit in terms of overall survival with the use of adjuvant chemotherapy, it is modest, perhaps akin to that of patients with resected non–small-cell lung cancer, and thus the risks and benefits of this toxic therapy should be discussed with patients on an individual basis.

Treatment recommendations

• Multidisciplinary treatment planning should precede the initiation of any therapy. An experienced multidisciplinary team should evaluate pathologic material and imaging studies and coordinate the integration of surgical resection, irradiation, and systemic therapy.

• Ideally, patients should be offered participation in clinical trials. Unfortunately, there are no active trials in the United States that will definitively answer the most important questions. Thus, a decision to treat must be made on an individual basis.

• Preoperative chemotherapy should be considered for fit, high-risk patients after a discussion of the risks and potential benefits; older patients, especially those with cardiac or renal disease, are not optimal candidates for such treatment.

• Patients who do not receive preoperative chemotherapy may still be offered postopertive treatment. Adjuvant anthracycline/ifosfamide combinations improve relapse-free survival in selected patients and can be considered for the treatment of those with tumor size > 5 cm, deep tumor location, and high histologic grade. Overall survival was superior in the most recent meta-analysis of patients receiving anthracycline-ifosfamide-based therapy, and this should be the standard combination to consider if adjuvant therapy is to be administered.

• For patients who opt for preoperative or postoperative chemotherapy, a regimen that includes doxorubicin (60 to 75 mg/m²) or epirubicin (120 mg/m²) plus ifosfamide (9 to 10 g/m²), given for a total of 4 to 6 cycles, is a reasonable choice for patients younger than age 60.

• Outside the context of a clinical trial, it is difficult to recommend concurrent doxorubicin and radiation therapy, or closely spaced doxorubicin-based chemotherapy with radiation therapy, owing to the observed risk of second malignancies such as AML in clinical trials to date.

Treatment of Local Recurrence

Despite optimal multimodality therapy, local recurrence develops in 10% to 50% of patients, with a median local recurrence-free interval of ~24 months. Local recurrence rates are a function of the primary site and are highest for patients with retroperitoneal and head and neck sarcomas, for which adequate surgical margins are difficult to attain. In addition, high-dose adjuvant irradiation of these sites is often limited by the relative radiosensitivity of surrounding structures. These factors result in local recurrence rates of 40% for retroperitoneal sarcomas and up to 50% for head and neck sarcomas, which are substantially higher than the 10% rate typically seen for extremity sarcomas.

A large retrospective analysis of patients with high-grade sarcoma of the extremities was reported from UCLA. Local recurrence required amputation in 38% of cases and was associated with a threefold decrement in survival. This finding accentuates the need for adequate local therapy for sarcomas presenting primarily as well as for multidisciplinary management of local recurrence.

Reoperation

Following staging evaluation, patients with isolated local recurrence should undergo reoperation. The results of reoperation in this setting are good, with two-thirds of patients achieving long-term survival.

Adjuvant radiation therapy

If no prior radiation therapy has been employed, adjuvant irradiation (50 to 65 Gy) should be used before or after surgery for locally recurrent disease. Radiation therapy (EBRT or brachytherapy) should be considered in patients for whom previous radiation doses were subtherapeutic or the previous radiation field design permitted additional treatment.

Reports from several referral centers suggest that patients who develop local recurrence following previous full-dose irradiation represent a difficult local tumor control challenge. A report from Memorial Sloan-Kettering Cancer Center suggests that limb-sparing surgery combined with adjuvant brachytherapy may produce excellent local tumor control and function in this group.

ILP

Ongoing clinical investigations are defining the role of isolated limb perfusion, or ILP, for the management of patients with locally recurrent sarcoma. ILP is approved in Europe for treatment of otherwise unresectable extremity sarcomas (see section on "Isolated limb perfusion").

Treatment of Limited Pulmonary Metastasis

Thoracotomy and metastasectomy

The most common site of metastatic disease involvement of soft-tissue sarcoma is the lungs. Rates of 3-year survival following thoracotomy for pulmonary metastasectomy range from 23% to 42%. This fact, combined with the limited efficacy of systemic therapy, is the basis for the recommendation that patients with limited pulmonary metastases and no extrapulmonary disease should undergo thoracotomy and metastasectomy.

Appropriate patient selection for this aggressive therapeutic approach to metastatic disease is essential. The following are generally agreed upon criteria: (1) the primary tumor is controlled or controllable; (2) there is no extrathoracic metastatic disease; (3) the patient is a medical candidate for thoracotomy; and (4) complete resection of all disease appears to be possible.

Preresection chemotherapy

Chemotherapy is sometimes recommended before resection of pulmonary metastases. Although occasional patients may have tumor shrinkage to a degree that an unresectable tumor becomes resectable, there are no convincing data that chemotherapy impacts favorably on patient survival. It is also notable that there are no randomized data on which to base this judgment.