Treatment of soft tissue sarcoma of the extremities

INTRODUCTION — Sarcomas are malignant tumors that arise from skeletal and extraskeletal connective tissues, including the peripheral nervous system. Sarcomas are rare with an estimated incidence in the United States of approximately 9,420 diagnosed annually, representing less than one percent of all newly diagnosed malignant tumors. The small number of cases seen and the great diversity in anatomic site, histopathology, and biology complicate understanding of the natural history of these tumors and their response to diverse therapies. As an example, there are only approximately 400 to 500 liposarcomas of the thigh (one histologic type at one anatomic site), diagnosed per year in the United States.

Local treatment for soft tissue sarcoma (STS) of the extremities will be reviewed here. The utility of adjuvant and neoadjuvant chemotherapy for extremity soft tissue sarcoma is discussed separately.. Treatment of soft tissue sarcoma in locations other than the extremities, and issues relating to classification, diagnosis, and staging are discussed separately.

SELECTION OF PRIMARY TREATMENT MODALITY — In treating STS of the extremities, the major therapeutic goals are survival, avoidance of a local recurrence, maximizing function, and minimizing morbidity. Surgical resection of the primary tumor is the essential component of treatment for virtually all patients. However, local control by surgery alone is poor unless the procedure removes large volumes of grossly normal tissue, ie, widely negative margins are attained. Sarcomas tend to infiltrate normal tissue adjacent to the evident lesion. Thus, removal of the gross lesion by a simple excision alone (only a narrow margin) is followed by local recurrence in 60 to 90 percent of patients. Compared to simple resection, radical resection of a wider margin of apparently normal tissue around the tumor reduces the local failure rate to approximately 25 to 30 percent . More recently, with the advent of compartmental resections, the local failure rate has fallen to 10 to 20 percent with surgery alone. One study that reported a zero local failure rate derives from the amputation arm of the National Cancer Institute trial comparing amputation to limb salvage treatment.

The combination of surgery and radiation achieves better outcomes than either treatment alone for nearly all STS. The rationale for combining radiation with surgery is to avoid the functional and cosmetic deformity associated with radical resection, and the late consequences of high radiation doses to large volumes of normal tissue in patients treated with primary radiation alone. Radiation at moderate dose levels (60 to 65 Gy) is as effective as radical resection in eradicating the microscopic extensions beyond the gross lesion, resulting in similar high rates of local control. This has allowed maximization of functional and cancer-related outcome without the significant morbidity of radical surgery. Most centers report local control rates of approximately 90 percent for high-grade extremity STS and 90 to 100 percent for low-grade STS depending upon the size.

In addition to its benefit in reducing local control rates, adjunctive radiotherapy has also had a significant impact on limb salvage for extremity sarcomas. As an example, in the 1970s, 50 percent of patients with extremity sarcoma underwent amputation; those patients treated by wide excision alone with limb preservation experienced a 30 percent rate of local recurrence (LR). With the subsequent application of radiotherapy and advanced reconstructive techniques, the rate of amputation at major centers has been reduced to less than 10 percent, and the incidence of LR with limb preservation has been reduced to 10 to 15 percent without any measurable fall in overall survival (OS). A single, prospective randomized trial showed similar rates of disease-free survival (DFS) and OS for patients treated with amputation or the combination of limb sparing surgery and radiotherapy for extremity STS.

Surgical resection — The success of a conservative surgical approach has, as mentioned above, resulted in an amputation rate at major centers of only 5 percent in patients with extremity STS. The current indications for amputation include: massive disease such that a functional limb is not achievable, as well as severely compromised normal tissues due to age, peripheral vascular disease, and other comorbidities. The functional and cosmetic results of conservative procedures are dependent upon the size and anatomic location of the tumor, the magnitude of the surgical procedure, extent to which muscles, tendons or nerves must be sacrificed, volume of tissues irradiated, and the radiation dose administered.

  The importance of resection margins — The most important surgical variable that influences local control is the presence or absence of tumor cells at the surgical margins. In series that report radical resection with clear margins, such as the Scandinavian Sarcoma Group, the local failure rates are quite low (8 percent). By contrast, in a second study of 559 patients who were treated with surgery alone from the same group, an inadequate surgical margin led to a 2.9-fold greater risk of LR than did clear surgical margins. Local recurrence, but not inadequate surgical margins, was a risk factor for distant metastasis (4.4-fold higher).

The status of the surgical margins also influences the local recurrence rate in patients treated with combined surgery and radiation.

  bullet In one review of 132 consecutive patients with STS of the extremities who were treated with preoperative radiation therapy followed by resection, the five year actuarial local control rates were 97 and 81 percent for patients with negative and positive margins respectively. Local control was not a function of sarcoma size in patients with negative surgical margins

  bullet In a second series of 1225 patients, all of whom received combined surgery and radiotherapy (either preoperative, postoperative or both), local control rates at five years were 88, 76, and 64 percent for patients with negative, uncertain, and positive margins, respectively.

The exact size of the negative margin that is optimal for local control is not known. In one study, the rate of local control did not differ in patients with a margin of less than or equal to1 or >1 mm (local control 96 versus 97 percent). Most clinicians recommend that if surgery is used as the sole modality of treatment, the margin should be at least 1 cm in all directions. If surgery is combined with radiation therapy, the surgical margin can probably be safely reduced to 0.5 cm without compromising the rate of LR.

The guiding principle of surgery is total en bloc excision of the primary tumor without cutting into tumor tissue. Tissues should be cut outside of the tumor pseudocapsule, if one exists, through normal uninvolved tissue. Violation of the tumor results in a higher local failure rate. In one report, for example, the local control rate in 95 patients with extremity STS was 47 percent if tumor violation occurred compared to 87 percent without violation.

The majority of STS do not involve bone; as a result, it is seldom necessary to resect adjacent bone. It is also rarely necessary to resect a major nerve unless the tumor is a neurogenic sarcoma. Nonamputative surgery is now accomplished in more than 90 percent of patients. If required, standard amputations are used (eg, below-knee for foot lesions, above-knee for large calf lesions, and hip disarticulation for large proximal thigh lesions).

  Reresection — In planning primary therapy for a patient who has had a suboptimal resection by a non-oncologic surgeon and/or insufficient imaging with preoperative CT or MRI, it is important to consider reresection. Approximately 37 to 68 percent of such patients will have residual tumor in a reresection specimen. A partial excision of the tumor before referral to a tertiary center does not appear to compromise limb preservation, local control, or survival rates in such patients although the reresection may entail a larger procedure than a de novo procedure and impact upon the functional result. In one series of 295 patients who underwent reresection at a single institution (final resection margins negative in 87 percent), local control rates at 5, 10, and 15 years were 85, 85, and 82 percent; the corresponding values for those who did not undergo reresection were 78, 73, and 73 percent, respectively  A similar degree of benefit for reresection was apparent for metastasis-free and disease-specific survival.

Radiation plus surgery — Our recommended treatment for patients who are medically and technically operable is the combination of surgery and radiation. In most instances, the probability of tumor control and the late functional and cosmetic result is clearly superior following the combined modality approach. Radiation is an effective treatment for STS, as the radiation sensitivity of cell lines derived from sarcomas is not less than that of epithelial cell lines. For small sarcomas, good local control rates can be achieved by radiation alone. However, local control probabilities of >90 percent for tumors of estimated volume 15 to 65 mL (approximately a sphere of 3 to 5 cm in diameter) requires high radiation doses (>75 Gy). As most treatment volumes are relatively large, the late normal tissue changes resulting from these dose levels are clinically important in nearly all patients. In animal models, a significantly lower radiation dose is required to achieve local control when radiation is combined with simple excision as compared to radiation alone.

The impact of combined modality treatment that includes external beam radiation (EBRT) on both local control and survival has been evaluated in only one prospective randomized trial. In this study, 91 patients with high-grade lesions were randomly assigned to surgery plus postoperative chemotherapy with or without postoperative adjuvant EBRT, and 50 with low-grade lesions were randomized to surgery plus adjuvant EBRT or surgery alone. In the patients with high-grade lesions, there were no LRs in the patients randomized to EBRT, while for those receiving only adjuvant chemotherapy, the actuarial local failure rate at ten years was 22 percent. For patients with low-grade sarcomas, the LR rates were 4 versus 33 percent in the postoperative EBRT and surgery alone groups, respectively. There was no influence of postoperative radiation on OS for either high or low grade tumors.

Preoperative versus postoperative radiotherapy — There are potential advantages to both preoperative (neoadjuvant) and postoperative (adjuvant) administration of radiation therapy. Preoperative radiation therapy might be expected to reduce tumor burden prior to resection, theoretically allowing more conservative surgical therapy. Postoperative radiotherapy allows histologic examination of the tumor specimen, especially the margins, aiding in further treatment planning; it may also be associated with fewer wound complications.

Retrospective uncontrolled series of patients who have received either postoperative or preoperative radiation have reported similar local control rates for either approach. As an example, in one review of 517 patients treated at a single institution between 1960 and 1999, the ten year local control rate was 72 percent among 246 patients treated with postoperative EBRT, and 83 percent in 271 who received preoperative EBRT. On multivariate analysis, this difference could be entirely explained by unequal distribution of prognostic factors in the two groups. Disease-specific survival was similar in both groups.

  Randomized Canadian trial — The only phase III clinical trial to evaluate this question was designed to evaluate the incidence of acute wound healing complications in patients with potentially curable extremity soft-tissue sarcoma. In this Canadian trial, 190 patients were randomly assigned to either preoperative (50 Gy preoperative for all 94 patients randomized to this arm with 16 to 20 Gy postoperative boost reserved for the 14 patients with a positive margin) or postoperative (50 Gy to the initial field plus 16 to 20 Gy boost for all patients) radiotherapy. Complications were defined as secondary wound surgery, hospital admission for wound care, or the need for deep packing or prolonged wound dressings within 120 days of tumor resection.

The study was terminated when a highly significant result was obtained at the time of a planned interim analysis. With a median follow-up of 3.3 years, a significantly higher percentage of preoperatively treated patients had acute wound complications (35 versus 17 percent). Other factors associated with acute wound complications were the volume of resected tissue and lower limb location of the tumor. Late morbidity was initially not reported. Because the radiation therapy fields for postoperative radiation therapy were larger and the dose delivered for most patients was higher, the authors indicated that longer follow-up would be needed to assess whether these larger radiation volumes and higher radiation doses would lead to more late treatment effects. In a later publication, the local recurrence rate, regional or distant failure rate, progression-free survival, and functional outcome did not differ between the groups.

These data have now been updated with a median follow-up of 6.9 years. There continues to be no difference in local control in the two arms of the study, with over 90 percent of patients controlled locally. The regional and distant failure rates as well as the progression-free and overall survival rates are also similar. However, patients treated postoperatively have developed significantly more grade 2 to 4 late toxicity than those treated preoperatively (86 versus 68 percent, respectively). In particular, the incidence of grade 3 (severe induration and loss of subcutaneous tissue or field contracture >10 percent linear measurement) or grade 4 (necrosis) subcutaneous fibrosis was significantly higher in the postoperative group (36 versus 23 percent, respectively).

Thus, the Canadian study demonstrates that efficacy is similar using the preoperative versus postoperative approach, and that the higher rate of generally reversible acute wound healing complications in preoperatively treated patients is offset by a lower rate of generally irreversible late complications, including grade 3-4 fibrosis. Because very few acute wound-healing complications occurred in either group with tumors located in the upper extremity, the authors suggested that these patients preferentially receive preoperative radiation therapy. However, we favor the preoperative approach for patients with lower extremity sarcomas as well, because acute wound complications can usually be managed and heal in the long-run, while the late treatment effects are generally irreversible.

New strategies are needed for patients with lower extremity sarcomas to reduce the risk of acute wound healing problems when preoperative radiation is administered, and to reduce the risk of late treatment induced effects when higher-dose, larger field post-operative radiation is given.

Brachytherapy — Compared to EBRT, brachytherapy (BRT) minimizes the radiation dose to surrounding normal tissues, maximizes the radiation dose delivered to the tumor, and shortens treatment times. In the usual dosage schedule, treatment is completed within six days and requires only one hospitalization. Afterloading catheters are placed in a target area of the tumor operative bed, defined by the surgeon, and spaced at 1 cm intervals to cover the entire area of risk.

A phase III trial of postoperative BRT versus no BRT was conducted in 126 patients who had complete resection of either extremity or superficial trunk STS. The BRT dose was 45 Gy. Five-year local control rates were 82 and 67 percent for the brachytherapy and surgery alone groups, respectively. The advantage of BRT was seen only in the high-grade sarcomas. It was limited to local control, since there was no difference between the groups in distant metastasis or disease-specific survival.

Radiation treatment planning — The radiation treatment technique should be carefully planned so that the tissues being irradiated are only those judged to be at risk. In order to utilize smaller treatment volumes, the part to be irradiated must be securely and reproducibly immobilized. We have special immobilization devices prepared for the individual patient. This may require casting, especially for hand, foot, or elbow sites. For some sites the part is placed in standard plastic supports and the extremity fastened tightly in place using a velcro fastener. Others describe their experience with casts and polyurethane foam systems.

The principal tasks involved in the development of a treatment plan are to:

  bullet Define the target volume (on each section of the CT/MRI of the affected region).
  bullet Define nontarget critical structures in the treatment volume and specify dose constraints for each such structure.
  bullet Estimate the distribution of number of tumor clonogens/unit volume of tissue throughout the target volume.
  bullet Define a series of target volumes to realize the appropriate dose distribution using "shrinking treatment volume methods".
  bullet Design an immobilization device and a means to assure that the target is on the beam.
  bullet Design treatment techniques which achieve the closest feasible conformation of treatment to target volume.

We use a "shrinking treatment volume technique" with a series of 2-4 progressively smaller volumes, the highest dose being administered to the tumor bed. Newer three dimensional (3-D) treatment planning systems appear to allow smaller and more accurate treatment volumes in patients with extremity STS.

To determine the proximal and distal margins (in the long axis of the extremity) of grossly normal tissue to be included for the first 50 Gy of EBRT, we use the following guideline according to histologic grade and size:

  bullet Small grade 1 — less than 5 cm
  bullet Larger, higher grade lesions — 5 cm

Boost field margins are generally 2 cm, and carried up to doses of 60 to 70 Gy, depending upon the surgical margin status.

The radial margin should be viewed with respect to the direction of most likely spread; the margin can be 2 cm where there is bone, interosseous membrane or major fascial planes and these planes are intact in the imaging studies. When a fascial plane has been violated, this 2 cm rule no longer applies and wider margins are appropriate.

This 2 cm radial margin is rationally derived from surgical experience. Local control rates are high when margins exceed 1 cm; the additional cm added to the radiation therapy margins allows for some daily set-up variation and the penumbra of the beam edge. The use of these 5 cm proximal and distal margins and 2 cm radial margins for the first 50 Gy (on the tumor for preoperative radiotherapy and the surgical bed for postoperative therapy) provided very high rates of local control in the randomized NCI Canada trial discussed above.

For treatment of an extremity lesion, a good functional result demands that only a portion of the cross section of the extremity be irradiated to any worthwhile dose level. Thus, some nonirradiated tissue should be left in order to provide for Iymphatic drainage. For very large tumors that were treated with wide resection, there may be persistent leg edema, requiring the use of a pressure-type stocking, even though the radiation treatment volume was less than circumferential. In our experience, this has been a common problem for patients with large (>10 cm) sarcomas of the medial thigh.

Combining postoperative radiation and chemotherapy has required reduction in the total radiation dose. We reduce the dose per fraction by 10 percent for patients who are to receive doxorubicin-based chemotherapy and do not give radiation concurrently with doxorubicin. Two to three days are allowed between the doxorubicin and radiation.

For patients receiving preoperative radiation, we administer 50 Gy over five weeks, wait 3 to 4 weeks, then perform a conservative resection. A boost dose to 66 Gy is given postoperatively or intraoperatively for microscopically positive margins, and to 75 Gy if there is gross residual disease. In patients with frozen section evidence of close or positive margins, an intraoperative boost dose is administered by BRT or electron beam. We prefer BRT and use a low dose rate of 16 Gy for microscopically positive margins, and 25 Gy for gross residual tumor.

Postoperative radiation usually begins 10 to 20 days following surgery. Following resection of large tumors, it may be necessary to wait three to four weeks to allow resorption of the seroma. The initial volume must include all tissues handled during the surgical procedure, including the drain site. The dose to the initial volume is 50 Gy and then through two subsequent treatment volumes the final dose is 60 Gy for negative margins, 66 to 68 Gy for positive margins or locally recurrent disease, and 75 Gy for gross residual sarcoma.

Neoadjuvant chemoradiotherapy for large high-grade lesions — Eilber et al at the University of California at Los Angeles (UCLA) initially popularized the combination of preoperative regional (intraarterial) chemotherapy plus radiation therapy followed by limb salvage surgery in patients with high-grade extremity sarcomas. They were able to achieve a high rate of primary limb salvage, low rate of local recurrence (approximately 9 percent) and long-term survival in 65 percent of patients. A number of other groups have obtained low rates of local recurrence using this regimen although it is not clear that intraarterial administration is necessary to achieve the synergistic effect of doxorubicin and radiation therapy. More recent efforts have explored administration of infusional intravenous doxorubicin concurrent with preoperative RT.

Combination chemotherapy regimens such as MAID (mesna, doxorubicin, ifosfamide, and dacarbazine, show table 5) may provide better antitumor activity than single agent doxorubicin. In particular, encouraging early results have been noted with neoadjuvant MAID plus radiation therapy:

  bullet Our experience with preoperative MAID chemotherapy interdigitated with 44 Gy radiation, and followed by surgery, postoperative MAID, and further radiation (16 Gy) for those with positive margins was reported in a series of 48 patients with high grade extremity sarcomas greater than or equal to8 cm. Despite the low objective response rate to preoperative therapy (partial response in five, stable disease in 36), all patients were able to undergo limb sparing surgery initially, with seven having positive margins. The median degree of tumor necrosis was 95 percent. Twenty-five percent of patients required hospitalization for febrile neutropenia at some time during treatment. Wound healing complications occurred in 14 of 48 MAID patients (29 percent), and one developed late fatal treatment-related myelodysplasia.

The five year rates of local control (92 versus 86 percent), freedom from distant metastases (75 versus 44 percent), disease-free survival (70 versus 42 percent), and overall survival (87 versus 58 percent) all compared favorably with the outcomes of a cohort of historical control patients who were matched for tumor size, grade, patient age, and era of treatment.

  bullet Similar results were noted when this regimen was utilized in a multicenter United States cooperative group trial, in which 66 patients with primary high grade soft tissue sarcoma greater than or equal to8 cm in diameter received a modified MAID regimen plus granulocyte colony-stimulating factor and radiation, followed by resection and postoperative chemotherapy. In a preliminary report, although preoperative chemotherapy and radiation was successfully completed by 79 and 89 percent of patients respectively, grade 4 hematologic and nonhematologic toxicity was experienced by 80 and 23 percent of patients. Delayed wound healing was noted in 31 percent. With a median follow-up of 2.75 years, the estimated three-year survival, disease-free survival and local control rates were 75, 55, and 79 percent, respectively. Two patients developed late myelodysplasia.

Although we favor this approach for high-grade extremity sarcomas of the extremity greater than or equal to8 cm, particularly if limb salvage is an issue, others prefer preoperative doxorubicin and ifosfamide-based chemotherapy alone for such patients.

SOFT TISSUE SARCOMAS OF THE HAND AND FOOT — The five-year survival rate for sarcoma of the hand and foot is approximately 80 percent, better than that usually given for extremity soft tissue sarcomas . With surgical excision and the use of adjunctive radiotherapy when the minimum surgical margin is narrow (less than 2 mm), limb amputation can be avoided as primary therapy in most patients, and up to two-thirds of patients can retain a normal or fairly normal extremity.

CHEST WALL SARCOMAS — Primary soft tissue sarcomas of the chest wall are rare, accounting for 10 percent or less of all soft tissue sarcomas. Some authors group these lesions with retroperitoneal and subcutaneous sarcomas, while others include them in the ill-defined term "truncal sarcomas". However, the clinical behavior of chest wall sarcomas is more similar to extremity sarcomas than to retroperitoneal sarcomas (which, like head and neck sarcomas, have a poorer prognosis). Their clinical behavior and prognostic factors are similar to those of extremity sarcomas, and they should be treated similarly. In one series of 55 patients treated for primary soft tissue sarcomas of the chest wall over a 32-year period, five-year overall and disease-free survival rates were 87 and 75 percent, respectively.

WOUND HEALING AFTER SURGERY AND RADIATION — In general, the use of adjunctive radiation is associated with a higher frequency of wound complications. Quantitation of the impact of radiation on wound healing is difficult because of the significant complications seen with surgery alone. In addition, there is much heterogeneity among patients with STS with respect to anatomic site, histologic type, lesion size, prior surgery, medical status, and age.

The use of adjunctive radiotherapy can also be associated with joint stiffness, edema, and decreased range of motion. In one trial, extremity radiation resulted in significantly worse limb strength, edema, and range of motion compared to surgery alone for extremity STS, but the symptoms were transient and did not affect global quality of life.

Preoperative radiation and wound complications — Preoperative radiation is associated with a higher incidence of acute wound complications than surgery alone or postoperative radiation. On the other hand, postoperative radiation is associated with a higher risk of late, often irreversible complications as compared to preoperative radiation leading many to conclude that preoperative treatment is preferable .

Strategies to reduce wound morbidity — Based upon our experience and the published experience of others, we suggest the following strategies to reduce wound morbidity in patients being treated with preoperative radiation or perioperative brachytherapy:

  bullet Gentle handling of tissue during surgery
  bullet Meticulous attention to achieving hemostasis before wound closure
  bullet Avoidance of closure under tension
  bullet Elimination of all wound dead space, using a rotated flap to fill the space, if necessary
  bullet Wound drainage with tubes remaining in place until drainage is decreasing in a satisfactory manner
  bullet Use of compression dressings
  bullet Immobilization of the affected part for approximately seven days
  bullet Delineation of a subgroup of patients where postoperative boost dose can be omitted (including those with negative margins and no tumor cut-through, complete necrosis of tumor, or absence of any residual tumor in the resection specimen)

In an attempt to select patients who may do well without radiotherapy, thereby avoiding wound complications, several published series have evaluated wide excision limb-sparing surgery alone.

  bullet In one report, 119 selected patients with extremity STS were grouped according to anatomic location as subcutaneous (n = 40), intramuscular (n = 30), or extramuscular (n = 49). The 70 patients with subcutaneous and intramuscular tumors were all treated by local surgery, and a wide margin, requiring a cuff of fat tissue around the tumor and inclusion of the deep fascia beneath the tumor, was obtained in 56. These patients were followed without postoperative radiation. During a median follow-up of five years (range, 3.5 to 10 years), only four had a local recurrence, despite the fact that 84 percent had high-grade tumors. The authors concluded that postoperative radiation may not be necessary in this subgroup.

  bullet In another study, 74 patients with localized STS of the extremity or trunk underwent function-sparing surgery without radiation. The overall ten year actuarial local control rate was 93 percent, and was dependent on the adequacy of surgical margins (87 versus 100 percent for patients with margins of <1 cm and greater than or equal to1 cm, respectively). The ten year survival rate was 73 percent. This approach may be appropriate for carefully selected patients with small (< 5 cm), superficial tumors that can be resected with all margins >1 cm.

POSTTREATMENT SURVEILLANCE — Since metastatic tumor to the lung can be resected and is frequently asymptomatic, we recommend frequent follow-up, particularly in the first two years after treatment, since two-thirds of recurrences will be detected during this period. Although posttreatment surveillance guidelines have not been established through rigorous clinical investigation , we follow patients with a history and physical examination at 3 to 4 month intervals for two years, four to six month intervals for 2 years, and yearly thereafter. We also perform imaging studies (CT scans of the chest and MRI imaging of the primary tumor site) at four to six month intervals for the first two years and then yearly for five years. Similar surveillance guidelines are suggested by the National Comprehensive Cancer Network (NCCN).

FUNCTIONAL OUTCOME — There are limited data on the functional outcome of patients undergoing limb salvage procedures. In one series of 88 patients treated with surgery and either preoperative or postoperative radiation therapy, 68 had acceptable functional results and 61 returned to work. Large tumors, neural sacrifice, proximal thigh tumors, and postoperative complications were associated with poor outcome.

In a single institution series of 145 patients who underwent limb-sparing surgery plus radiation therapy, long term treatment complications included bone fracture in 6 percent, contracture in 20 percent, significant edema in 19 percent, moderate to severe decrease in muscle strength in 20 percent, requirement for a cane or crutch in 7 percent and tissue induration in 57 percent [73]. Three patients (2 percent) required amputations for treatment-related complications. The percentage of patients ambulating without assistive devices and with mild or no pain was 84 percent. Higher doses of radiation therapy, a long radiation portal, and irradiation of more than 75 percent of the extremity diameter were associated with increased complications.

A third study also examined issues related to quality of life in patients with STS of the lower limb [72]. Although radiation therapy was associated with reduced muscle power and range of motion, compared to the use of surgery alone, most patients retained good to excellent limb function and quality of life.

The functional outcome is often not as good in patients requiring amputation. In a matched case-control study of patients with lower extremity sarcoma undergoing amputation (n = 12) or a limb-sparing approach (n = 24), there was a trend toward increased disability and handicap for those in the amputation group. Seven of the 12 amputees reported ongoing problems with the soft tissue overlying the stump.

A few studies have assessed quality of life issues in amputees who had been treated for STS with amputation and chemotherapy compared with patients who underwent limb salvage with radiotherapy and chemotherapy. Contrary to expectations, there were no significant differences in measures of psychologic outcome. Thus, a psychologic advantage of limb-salvage surgery compared to amputation has yet to be demonstrated.

TREATMENT OF LOCAL RECURRENCE — Approximately 10 to 15 percent of patients with extremity STS who are treated with complete resection and adjuvant radiation will develop a local tumor failure, the majority within the first two years .The approach to the patient with an isolated local recurrence is similar to that for primary disease with some modification.

Surgical management of locally recurrent disease — As with primary treatment, the goal is to provide limb salvage with conservative resection. However, approximately 10 to 25 percent of patients with locally recurrent disease will require amputation .. Surgery is an important component of successful salvage therapy . For patients whose primary treatment was surgery alone, reexcision combined with postoperative radiation is the treatment of choice. If radiation therapy was used in primary treatment, further radiation may not be possible because the maximal tolerance for adjacent normal tissues would have to be exceeded, resulting in problems in wound healing and radiation fibrosis, although additional radiation given by brachytherapy (mean dose 47.2 Gy) has been employed in these cases with a 52 percent local control and a 33 percent disease-free survival in one series of 26 patients.

Optimal treatment for a local recurrence may require both surgery and radiation. This was illustrated in one report of salvage therapy using surgery alone or surgery plus reirradiation for 25 patients with locally recurrent extremity STS. Eighteen patients underwent surgery alone, 11 treated by a conservative procedure and seven requiring amputation. Seven of these 18 relapsed. Of the 10 treated with surgery plus radiation, none experienced relapse with a median follow-up of 24 months. Six (60 percent) experienced significant wound healing complications, but three recovered completely.

TREATMENT OF UNRESECTABLE OR LOCALLY ADVANCED SOFT TISSUE SARCOMA — In patients with advanced STS in whom the tumor has progressed beyond surgical resectability, treatment options depend upon the site of tumor involvement. For patients with unresectable disease limited to the extremity, isolated limb perfusion (ILP) protocols have been applied with striking early success. Selected patients can achieve local control with radiation therapy with or without chemotherapy, especially if the tumor is small. In other cases, systemic chemotherapy remains the only option for treatment with the exception of patients with isolated pulmonary metastases who may be candidates for resection.

Isolated limb perfusion with tumor necrosis factor alpha — Recombinant tumor necrosis factor-alpha (TNF-alpha) is a highly potent antineoplastic agent. Systemic administration in humans results in a life-threatening septic shock-like syndrome. However, the administration of high dose TNF-alpha and melphalan via ILP eliminates the systemic side effects and allows the delivery of a dose of TNF that is 10-fold the maximally tolerated systemic dose. Several studies have reported encouraging data on the use of ILP with high dose TNF-alpha and melphalan in patients with unresectable extremity STS.

In the largest multi-institutional study, 140 patients underwent therapy with TNF-alpha and melphalan with (TIM, n = 55) or without (TM, n = 75) interferon alpha followed by surgery. A response rate of 87 percent was obtained with TIM and 82 percent with TM; limb salvage rates were 82 and 81 percent respectively. Limb salvage was obtained in patients with very locally advanced disease. Systemic toxicity was moderate and included fever, chills, and a hyperdynamic cardiac state.

This procedure is complex and warrants further study for advanced extremity STS. When ILP is combined with adjuvant external beam radiotherapy and delayed tumor resection, local tumor control may be increased but there appears to be a considerable risk of tissue necrosis and impaired healing .

Other therapies for locally advanced disease — Several centers have reported local control rates of approximately 50 percent with fast neutron irradiation of inoperable STS. In addition, several potent radiation sensitizers have been used to treat patients with extensive sarcoma with promising early preliminary results .

SUMMARY AND RECOMMENDATIONS — Treatment for STS requires individual tailoring of the approach because of the wide variety of clinical situations that can arise from a tumor that involves a variety of anatomic sites, the range of histologies, and the variability in grade and tumor size. Nevertheless, the following suggestions can serve as useful guides.

Surgery is always indicated but the use of adjuvant therapy can vary according to the anatomic site, size, and histologic grade. We recommend the following approach:

  bullet In general, surgical excision alone is appropriate for patients with superficial low-grade tumors that are less than 5 cm in diameter. Such patients can expect excellent local control and survival rates approximating 90 percent.

  bullet For intermediate-grade lesions, surgical excision with negative margins in combination with radiotherapy has achieved excellent local control with overall survival rates approximating 80 percent. For larger, deep-seated tumors, preoperative radiation therapy is preferred over postoperative radiation.

  bullet For patients with high-grade STS larger than 5 cm, excellent local control can be achieved with surgery and radiotherapy, but at least 50 percent of these patients will develop metastatic disease. In this setting, the use of neoadjuvant chemotherapy may benefit some and should be considered, preferably in the context of a clinical trial. Off-protocol, we prefer the interdigitated MAID/RT regimen, although others prefer chemotherapy first followed by RT then surgery.


  bullet The benefit of adjuvant chemotherapy following optimal local therapy remains uncertain. This approach cannot be adopted as the standard of practice for all extremity soft tissue sarcomas.

  bullet For patients with locally recurrent disease, reresection should be considered, if possible. Radiation therapy is rarely curative, particularly if the recurrence develops in a previously irradiated site. Isolated limb perfusion is a potentially limb-preserving option, but the treatment protocol is complex and expertise is limited to specialized cancer centers.