Soft-Tissue Sarcomas

Treatment

Treatment of Localized Disease

Surgical resection is the cornerstone of therapy for patients with localized disease. After 1980, there was a gradual shift in the surgical management of soft-tissue sarcoma of the extremities away from radical ablative surgery, such as amputation or compartment resection, toward limb-sparing approaches combining wide local resection with preoperative or postoperative radiotherapy. The development of advanced surgical techniques (eg, microvascular tissue transfer, bone and joint replacement, and vascular reconstruction) and the application of multimodality approaches have allowed most patients to retain a functional extremity without any compromise in survival.

Surgery

The surgical approach to soft-tissue sarcomas depends on careful preoperative staging with MRI or CT for lesions of the extremities and a percutaneous histologic diagnosis and assessment of tumor grade. In most instances, preoperative imaging studies allow for accurate prediction of resectability.

The surgical approach to soft-tissue sarcomas is based on an awareness that these lesions tend to expand and compress tissue planes, producing a pseudocapsule.

Wide local resection. Wide local resection encompassing a rim of normal tissue around the lesion has led to improvements in local tumor control, with local recurrence rates of approximately 30% in the absence of adjuvant therapies. However, studies indicate that carefully selected patients with localized, small (T1), low-grade soft-tissue sarcomas of the extremity can be treated by wide resection alone, with local recurrence rates of < 10%.

A prospective trial examined local recurrence rates for T1 primary soft-tissue sarcomas of the trunk and extremities. Patients underwent function-preserving surgery. Postoperative radiation was delivered for microscopically positive margins (R1 resection). No radiation was delivered if margins were negative (R0 resection). A total of 88 patients were evaluated in this trial. A total of 16% had R1 resection and received adjuvant radiation therapy, whereas 84% had R0 resection and did not receive radiation therapy. With a median follow-up of 75 months, isolated local recurrence was observed in six patients in the R1 arm (43%) and six patients in the R0 arm (8%). The 5- and 10-year local recurrence rates in the R0 arm were 7.9% and 10.6%, respectively, and the sarcoma-specific death rates were 3.2% at both 5 and 10 years in the R0 arm.

The need for adjuvant irradiation in small (< 5 cm), high-grade lesions has been studied. A retrospective review of 204 patients with stage IIB soft-tissue sarcoma of the extremity treated at Memorial Sloan-Kettering Cancer Center yielded a total of 57% of patients who did not receive adjuvant radiation therapy, whereas 43% received either brachytherapy or external-beam radiation therapy (EBRT). With a median follow-up of 67 months, there was no significant difference in 5-year local tumor control, distant relapse–free survival, or disease-specific survival when adjuvant irradiation was delivered.

Further studies will be required to define which subsets of patients with primary extremity sarcoma can be treated by wide excision surgery alone. Preoperative or postoperative radiotherapy should be employed for patients with primary T1 sarcomas in whom a satisfactory gross surgical margin cannot be attained without compromise of functionally important neurovascular structures.

Limb-sparing surgery plus irradiation. Limb-sparing surgery employing adjuvant irradiation to facilitate maximal tumor local control has become the standard approach for large (T2) soft-tissue sarcomas of the extremities. In most centers, more than 90% of patients are treated with limb-sparing approaches. Amputation is reserved as a last-resort option for local tumor control and is used with the knowledge that it does not affect survival. This approach was validated in a prospective National Cancer Institute (NCI) study, in which patients with a limb-sparing surgical option were randomized to receive limb-sparing surgery with postoperative radiation therapy or amputation. Both arms of the study included postoperative therapy with doxorubicin(Drug information on doxorubicin), cyclophosphamide(Drug information on cyclophosphamide), and methotrexate(Drug information on methotrexate).

Surgical procedure. The planned resection should encompass the skin, subcutaneous tissues, and soft tissues adjacent to the tumor, including the previous biopsy site and any associated drain sites. The tumor should be excised with a 2- to 3-cm margin of normal surrounding tissue whenever possible. Since good adjuvant approaches are available to facilitate local tumor control, the surgeon sometimes compromises this ideal margin rather than attempting resection of adjacent, possibly involved bone or neurovascular structures that would result in significant functional loss. In the rare circumstance of gross involvement of neurovascular structures or bone, en bloc resection and reconstruction can be performed.

Metal clips should be placed at the margins of resection to facilitate radiation field planning, when and if external irradiation is indicated. Drain sites should be positioned close to the wound to allow inclusion in radiation therapy fields. As noted earlier, avoidance of transverse incisions greatly facilitates the ability to include the tissues at risk in the radiation target volume without unduly large fields.

Regional lymphadenectomy. Given the low (2% to 3%) prevalence of lymph node metastasis in adult sarcomas, there is no role for routine regional lymphadenectomy. Patients with angiosarcoma, embryonal rhabdomyosarcoma, synovial sarcoma, and epithelioid histologies have an increased incidence of lymph node metastasis and should be carefully examined and are good candidates for sentinal lymph node biopsy. Clinically apparent lymphadenopathy should be treated with therapeutic lymphadenectomy. A recent analysis suggested that select patients undergoing lymphadenectomy, particularly in the absence of systemic metastases, may have a 5-year survival rate superior to the survival expected for patients with AJCC stage IV disease, as was defined in AJCC version 6. As a result, the AJCC staging system (version 7) for sarcomas suggests that patients with lymph node metastasis should be considered in a different category from patients with overt blood-borne metastases.

Radiotherapy

Radiation therapy is usually combined with surgical resection in managing soft-tissue sarcomas of the extremities.

Preoperative irradiation. Preoperative irradiation has a number of theoretic and practical advantages: (1) Smaller radiation portals can be utilized, as the scar, hematomas, and ecchymoses do not need to be treated. (2) Preoperative irradiation may produce tumor encapsulation, facilitating surgical resection from vital structures. (3) It is easier to spare a strip of skin and thereby reduce the risk of lymphedema. (4) The size of the tumor may be reduced, thus decreasing the extent of surgical resection. (5) Lower radiation doses can be utilized, as there are fewer relatively radioresistant hypoxic cells.

Preoperative irradiation also has several drawbacks, however. They include (1) the inability to precisely stage patients based on pathology due to downstaging and (2) increased problems with wound healing.

Studies of preoperative irradiation from the University of Florida, the University of Texas MD Anderson Cancer Center, and Massachusetts General Hospital demonstrated local tumor control rates of 90% using doses of approximately 50 Gy. Survival depended on the size and the grade of the primary tumor. Distant metastases were the primary pattern of failure.

Postoperative irradiation. A number of retrospective reports, as well as a randomized trial from the NCI, have demonstrated that limb-sparing surgery plus postoperative irradiation produces local tumor control rates comparable to those achieved with amputation. Five-year local tumor control rates of 70% to 90%, survival rates of 70%, and limb-preservation rates of 85% can be expected.

Equivocal or positive histologic margins are associated with higher local recurrence rates, and, therefore, adjuvant external-beam irradiation should be considered in all patients who have sarcoma of the extremities with positive or close microscopic margins in whom reexcision is impractical. Postoperative doses of 60 to 65 Gy should be used.

Interstitial therapy. Interstitial therapy with iridium-192 is used at some institutions as a radiation boost to the tumor bed following adjuvant external-beam irradiation. In a randomized trial, the 5-year local tumor control rate was 82% in patients who received adjuvant brachytherapy vs 69% in those treated with surgery alone. On subset analysis, the local tumor control rate was found to be 89%, vs 66% for patients with high-grade lesions. This study and additional studies have indicated that brachytherapy has no impact on local tumor control for low-grade lesions.

FIGURE 1AKaplan-Meier plots for probability of local recurrence in the National Cancer Institute of Canada Clinical Trials Group phase III trial.

FIGURE 1BKaplan-Meier plots for probability of overall survival in the National Cancer Institute of Canada Clinical Trials Group phase III trial.

If an implant alone is used, the dose is 40 to 45 Gy to a volume that includes all margins; when a boost is combined with additional external-beam irradiation, a dose of 20 to 25 Gy is utilized. Some data suggest a higher rate of wound complications and a delay in healing when implants are afterloaded prior to the third postoperative day. Although some centers load implants sooner, this step must be performed with caution and strict attention to the incision site.

Over a 15-year period, 202 patients with high-grade sarcoma of the extremities underwent complete gross resection and adjuvant brachytherapy to a median dose of 45 Gy, delivered over 5 days. With a median follow-up of 61 months, the 5-year local tumor control, distant relapse-free survival, and overall survival rates were 84%, 63%, and 70%, respectively. These rates compared favorably with data on external-beam irradiation. Morbidity of brachytherapy was considered acceptable, with reoperation rates of 12%, bone fractures in 3%, and nerve damage in 5%.

Comparison of irradiation techniques. Comparable local tumor control results (90%) are obtained with preoperative, postoperative, and interstitial techniques, although rates of wound complications are higher with preoperative techniques. Brachytherapy can offer a number of advantages. When brachytherapy is employed as the sole adjuvant (ideally in R0 cases), the entire local therapy (surgery plus radiation) is completed in a 10- to 12-day period. This compares favorably to the 3-month period reqiured for surgery, postoperative recovery (6-8 weeks), and external beam radiation treatment (6 weeks). Generally, smaller volumes can be irradiated with brachytherapy, which could improve functional results. However, smaller volumes may not be appropriate, depending on the tumor size, grade, and margin status.

The NCI of Canada Clinical Trials Group published 3-year median follow-up results of a randomized phase III trial comparing preoperative and postoperative radiotherapy for limb soft-tissue sarcoma (Figures 1A, 1B). Wound complications were observed in 31 of 88 patients (35%) in the preoperative group and 16 of 94 patients (17%) in the postoperative group (difference, 18% [95% CI: 5–30]; P = .01). Tumor size and anatomic site were also significant risk factors in multivariate analysis. Local tumor control was identical in both arms of the trial. Five-year outcomes have been reported, and no difference in metastases, cause-specific survival, or overall survival was noted. Because preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy, but less late fibrosis and edema, 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.

Regardless of the technique employed, local control is a highly achievable and worthwhile endpoint, as demonstrated in a retrospective study of 911 patients treated by various techniques at Memorial Sloan-Kettering Cancer Center. Of the 116 patients who developed local recurrence, 38 patients subsequently developed metastases and 34 patients died. Metastases after local recurrence were predicted in patients with high-grade or large (> 5 cm) tumors.

Treatment recommendations. Adjuvant radiotherapy should be employed for virtually all high-grade sarcomas of the extremities and larger (≥ 5 cm) low-grade lesions. If small (T1) lesions can be resected with clear margins, radiotherapy may be omitted. Postoperative therapy with either external-beam irradiation (with or without an interstitial implant boost) or an implant alone will achieve a high likelihood of local tumor control and, therefore, limb preservation. Preoperative irradiation, although equally efficacious, does carry a higher wound complication rate than the postoperative approach. For smaller tumors under 5 cm in more difficult anatomic sites such as the head and neck, consideration can still be given to neoadjuvant or adjuvant radiation therapy, given the implications of local recurrence in these anatomic sites.

Primary radiation therapy

Several studies of radiation therapy alone in the treatment of unresectable or medically inoperable soft-tissue sarcomas have reported 5-year survival rates of 25% to 40% and local tumor control rates of 30%. Local tumor control depends largely on the size of the primary tumor. Radiation doses should be at least 65 to 70 Gy, if delivery of such doses is feasible. The tumor's location may be particularly important in determining this dose because of the potential for damage to critical structures (eg, the spinal cord) with the higher doses normally used. Image-guided techniques with EBRT may make it possible to deliver an even higher dose to such tumor beds, as can particulate radiation such as proton beam therapy.

Radiation therapy in retroperitoneal sarcomas

Only 50% of patients with retroperitoneal sarcomas are able to undergo complete surgical resection. Of patients undergoing complete resection, well over half will develop local recurrence. This significant local failure rate suggests a potentially important role for adjuvant treatment in all patients with retroperitoneal sarcomas. However, the role of radiation therapy for retroperitoneal sarcomas remains controversial due to the rarity of the tumor, the paucity of data, the retrospective nature of available studies, the low doses of radiation used in many studies, and the lack of consistent policies for determining the indications for radiation therapy.

Preoperative irradiation. The advantages of preoperative radiotherapy have already been discussed for soft-tissue sarcomas of the extremities. In the retroperitoneum, an additional advantage is that bowel is frequently displaced significantly by the tumor. In contrast to the postoperative setting, the bowel being treated is also unlikely to be tethered by adhesions from prior surgery. These features significantly offset acute toxicity of large-field intra-abdominal radiotherapy (eg, nausea, vomiting, and diarrhea) as well as the potential for late-onset bowel toxicity. Conformal techniques capable of sparing normal tissues are also more easily applied in the preoperative setting, when the tumor can be visualized and the target area more readily defined.

Intraoperative irradiation. In a prospective trial from the NCI, 35 patients with completely resected retroperitoneal sarcomas were randomized to receive either intraoperative electron-beam irradiation (IORT) followed by low-dose (30 to 40 Gy) postoperative EBRT or high-dose postoperative EBRT (35 to 40 Gy plus a 20-Gy boost). Absolute local recurrence rates were significantly lower in the IORT group (P < .05), but disease-specific and overall survival rates did not differ between the two groups.

Similarly, a nonrandomized series from the Massachusetts General Hospital has suggested improved local tumor control with IORT for patients with retroperitoneal sarcoma. In 16 patients who underwent irradiation, complete gross resection, and IORT, overall survival and local tumor control rates were 74% and 83%, respectively. These numbers diminished to 30% and 61%, respectively, in the 13 patients treated with irradiation and complete gross resection without IORT. Although these local tumor control results are encouraging, IORT remains investigational and cannot be advocated on a routine basis at this time.

Postoperative irradiation. Two-year local tumor control rates of 70% have been reported with the addition of postoperative irradiation. However, irradiation of the retroperitoneum/abdomen in doses that have effected local tumor control in soft-tissue sarcoma of the extremities (50 to 65 Gy) is usually associated with significant GI toxicity. Obviously, the incidence of GI toxicity depends on the exact fields and technique used. However, as most retroperitoneal sarcomas are > 10 to 15 cm, the radiation fields employed are generally also quite large, and bowel is often located and/or tethered in the high-risk area. Three-dimensional treatment planning and conformal techniques can now be utilized to maximize the radiation dose to the tumor bed while minimizing the dose to the surrounding normal tissues.

Isolated limb perfusion

Recent studies have evaluated the role of isolated limb perfusion (ILP) in the management of sarcomas of the extremities. These studies have generally been extrapolations from protocols initially designed to treat locally advanced melanoma.

The agents most commonly employed for ILP have been melphalan(Drug information on melphalan) and tumor necrosis factor-alpha, with or without interferon-gamma (IFN-γ-1b [Actimmune]). The results of the largest series of ILP in patients with locally advanced soft-tissue sarcoma of the extremities were reported by Eggermont and colleagues. TNF-α has now been approved in Europe for ILP in patients with locally advanced intermediate-high grade soft-tissue sarcomas of the extremities.

The Netherlands Cancer Institute published its results in patients with unresectable soft-tissue sarcoma of the extremities who were perfused with melphalan and TNF-α. A total of 49 patients were treated and followed for a median of 26 months. One patient died shortly after perfusion, but 31 patients (63%) were able to undergo resection of the tumor. Based on clinical and pathologic grounds, an overall response was seen in 31 patients (63%), and a complete response was seen in 4 patients (8%). A total of 28 patients (57%) had local tumor control with limb preservation. Toxicity was frequent but usually mild, with post-treatment edema being a common complication.