Soft-tissue Sarcomas

The soft-tissue sarcomas are a group of rare but anatomically and histologically diverse neoplasms. This is due to the ubiquitous location of the soft tissues and the nearly three dozen recognized histologic subtypes of soft-tissue sarcomas. In the United States, 7,800 new cases of soft-tissue sarcoma are identified annually, and 4,400 patients die of the disease each year. The age-adjusted incidence is 2 cases per 100,000 persons.

Epidemiology

Unlike the more common malignancies, such as colon cancer, little is known about the epidemiology of soft-tissue sarcomas. This, again, reflects the uncommon nature of these lesions.

Gender There is a slight male predominance, with a male to female ratio of 1.1:1.0.

Age The age distribution in adult soft-tissue sarcoma studies is: < 40 years, 20.7% of patients; 40-60 years, 27.6% of patients; > 60 years, 51.8% of patients.

Race Studies in large cohorts of patients demonstrate that the race distribution of soft-tissue sarcomas mirrors that of the US population (86% Caucasian, 10% African-American, 1% Asian-American).

Geography Studies have suggested that the incidence and mortality of soft-tissue sarcomas may be increasing in New Zealand. There are no currently available data addressing this possibility in the United States.

Etiology and risk factors

In the majority of cases of soft-tissue sarcoma, no specific etiologic agent is identifiable. However, a number of predisposing factors have been recognized.

Radiation therapy Soft-tissue sarcomas have been reported to originate in radiation fields following therapeutic radiation for a variety of solid tumors. By definition, radiation-induced sarcomas arise no sooner than 3 years after radiation therapy and often develop decades later. The majority of these sarcomas are high-grade lesions (90%), and osteosarcoma is a predominant histology. Malignant fibrous histiocytoma (MFH), angiosarcoma, and other histologic subtypes have also been reported.

Chemical exposure Exposure to various chemicals in specific occupations or situations has been linked with the development of soft-tissue sarcoma. These include the phenoxy acetic acids (forestry and agriculture workers), chlorophenols (sawmill workers), Thorotrast (diagnostic x-ray technicians), vinyl chloride (individuals working with this gas, used in making plastics and as a refrigerant), and arsenic (vineyard workers).

Chemotherapy Soft-tissue sarcomas have been reported after previous exposure to alkylating chemotherapeutic agents, most commonly after treatment of pediatric acute lymphocytic leukemia. The drugs implicated include cyclophosphamide (Cytoxan, Neosar), melphalan (Alkeran), procarbazine (Matulane), nitrosoureas, and chlorambucil (Leukeran). The relative risk of sarcoma appears to increase with cumulative drug exposure.

Chronic lymphedema Soft-tissue sarcomas have been noted to arise in the chronically lymphedematous arms of women treated with radical mastectomy for breast cancer (Stewart-Treves syndrome). Lower extremity lymphangiosarcomas have also been observed in patients with congenital lymphedema or filariasis complicated by chronic lymphedema.

Trauma and foreign bodies Although a recent history of trauma is often elicited from patients presenting with soft-tissue sarcoma, the interval between the traumatic event and diagnosis is often short; thus, a causal relationship is unlikely. Chronic inflammatory processes, however, may be a risk factor for sarcoma. Foreign bodies, such as shrapnel, bullets, and foreign body implants, have also been implicated.

Signs and symptoms

Signs and symptoms of soft-tissue sarcoma depend, in large part, on the anatomic site of origin. Due to the ubiquitous location of the soft tissues, these malignancies may arise at any site in the body where soft tissues are located. Since 50% of soft-tissue sarcomas arise in an extremity, the majority of patients present with a palpable soft-tissue mass. Pain at presentation is noted in only one-third of cases.

Extremity and superficial trunk Extremity and superficial trunk sarcomas account for 60% of all soft-tissue sarcomas. The majority of patients present with a painless primary soft-tissue mass.

Retroperitoneum Retroperitoneal sarcomas account for 15% of all soft-tissue sarcomas. Most patients (80%) present with an abdominal mass, with 50% reporting pain at presentation. Due to the considerable size of the retroperitoneum and the relative mobility of the anterior intra-abdominal organs, these tumors often grow to substantial size before the patient’s nonspecific complaints are evaluated or an abdominal mass is noted on physical examination.

Viscera Visceral soft-tissue sarcomas, which comprise 15% of all soft-tissue sarcomas, present with signs and symptoms unique to their viscus of origin. For example, GI leiomyosarcomas present with GI symptoms that are usually indistinguishable from the more common adenocarcinomas. Similarly, uterine leiomyosarcomas frequently present with painless vaginal bleeding like that often noted in patients with more common uterine malignancies.

Pathology

Histopathologic classification As a consequence of the wide spectrum of soft tissues, a variety of histologically distinct neoplasms have been characterized. The current histopathologic classification is based on the putative cell of origin of each lesion. Such classification based on histogenesis is reproducible for the more differentiated tumors. However, as the degree of histologic differentiation declines, it becomes increasingly difficult to determine cellular origin.

In addition, many of these tumors dedifferentiate. This results in a variety of overlapping patterns, making uniform classification difficult. Experienced soft-tissue pathologists frequently disagree on the cell of origin of an individual tumor. Comparative studies have demonstrated concordance in histopathologic diagnosis in only two-thirds of cases.

Assignment of a specific histologic subtype is of secondary importance. This is because, with the possible exceptions of certain small-cell sarcomas, rhabdomyosarcoma, fibrosarcoma, and some forms of angiosarcoma, histogenesis is not directly related to biological behavior. The propensity for distant metastases and disease-related mortality are best predicted on the basis of histologic grade and tumor size.

Staging and prognosis

The relative rarity of soft-tissue sarcomas, the anatomic heterogeneity of these lesions, and the presence of more than 30 recognized histologic subtypes of variable grade have made it difficult to establish a functional system that can accurately stage all forms of this disease. The recently revised staging system (5th edition) of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is the most widely employed staging classification for soft-tissue sarcomas (Table 1). All soft-tissue sarcoma subtypes are included, except dermatofibrosarcoma protuberans. Four distinct histologic grades are recognized, ranging from well differentiated to undifferentiated.

Histologic grade and tumor size are the primary determinants of clinical stage. Tumor size is further substaged as “a” (a superficial tumor that arises outside the investing fascia) or “b” (a deep tumor that arises beneath the fascia or invades the fascia).

The AJCC/UICC system is designed to optimally stage extremity tumors but is also applicable to torso, head and neck, and retroperitoneal lesions. It should not be used for sarcomas of the GI tract.

A major limitation of the current staging system is that it does not take into account the anatomic site of soft-tissue sarcomas. Anatomic site, however, is an important determinant of outcome. Patients with retroperitoneal and visceral sarcomas have a worse overall prognosis than do patients with extremity tumors. Although site is not incorporated as a specific component of any current staging system, outcome data should be reported on a site-specific basis.

A thorough understanding of the clinicopathologic factors known to impact outcome is essential in formulating a treatment plan for the patient with soft-tissue sarcoma. Among the many reports evaluating prognostic factors in this disease, three detailed analyses merit discussion.

The initial study of prognostic factors in extremity sarcoma from Memorial Sloan-Kettering Cancer Center evaluated clinicopathologic prognostic factors in 423 patients with localized extremity soft-tissue sarcoma seen from 1968 to 1978. This analysis clearly established the clinical profile of what is now accepted as the high-risk patient with extremity soft-tissue sarcoma: an individual with a large ( ł 5 cm), high-grade, deep lesion. The adverse prognostic significance of high tumor grade, deep tumor location, and tumor size ł 5 cm was also noted in a 1996 French Federation of Cancer Centers study of 546 patients with sarcomas of the extremities, head and neck, trunk wall, retroperitoneum, and pelvis.

A follow-up report from Memorial Sloan-Kettering evaluated clinicopathologic prognostic factors that had been documented prospectively in 1,041 patients with extremity soft-tissue sarcoma. The end points for multivariate analysis were local recurrence, distant recurrence (metastasis), and disease-specific survival. Using prospectively acquired data, the analysis confirmed the association between large, high-grade, deep lesions and adverse outcome. In addition, the previously unappreciated prognostic significance of certain specific histologic subtypes and the increased risk for adverse outcome associated with a microscopically positive surgical margin or presentation with locally recurrent disease were noted.

Prognostic factors for local vs distant recurrence Unlike other solid tumors, the adverse prognostic factors for local recurrence of a soft-tissue sarcoma differ from those that predict distant metastasis and tumor-related mortality. In other words, patients with a constellation of adverse prognostic factors for local recurrence are not necessarily at increased risk for distant metastasis or tumor-related death. Therefore, staging systems that are designed to stratify patients for risk of distant metastasis and tumor-related mortality using these prognostic factors (such as the AJCC/UICC system) do not stratify patients for risk of local recurrence.

Screening and diagnosis

Since the majority of patients with soft-tissue sarcoma have lesions arising in the extremities or superficial trunk, most of the comments below apply to soft-tissue lesions in those sites. A separate algorithm is usually employed for the evaluation of a primary retroperitoneal mass or visceral sarcoma.

Physical examination should include an assessment of the size of the mass and its mobility relative to the underlying soft tissues. The relationship of the mass to the investing fascia of the extremity (superficial vs deep) and nearby neurovascular and bony structures should be noted. Site-specific neurovascular examination and assessment of regional lymph nodes should also be performed.

Biopsy Any soft-tissue mass in an adult should be biopsied if it is symptomatic or enlarging, is > 5 cm in size, or has persisted beyond 4-6 weeks.

Percutaneous approaches Percutaneous tissue diagnosis can usually be obtained with fine-needle aspiration (FNA) for cytology or by percutaneous core biopsy for histology. The needle track should be placed in an area to be excised. In most instances, when an experienced cytopathologist and/or histopathologist examines the specimen, a diagnosis of malignant soft-tissue sarcoma can be made. Histology is usually preferred to cytology, as more tissue is obtained for accurate delineation of tumor type and grade. Percutaneous tissue diagnosis is preferred to facilitate subsequent treatment planning and to permit surgical resection to be performed as a one-stage procedure.

Open biopsy In some cases, an adequate histologic diagnosis cannot be secured by percutaneous means. Open biopsy is indicated in these instances, with the exception of relatively small superficial masses, which can be easily removed by excisional biopsy with clear margins.

Biopsies should be incisional and should be performed with a longitudinal incision parallel to the long axis of the extremity. This facilitates subsequent wide local excision of the tumor and the incisional scar with minimal difficulties in wound closure. The incision should be centered over the mass at its most superficial location. Care should be taken not to raise tissue flaps. Meticulous hemostasis should be ensured after the biopsy to prevent dissemination of tumor cells into adjacent tissue planes by hematoma.

Retroperitoneal mass Biopsy of primary retroperitoneal soft-tissue masses is generally not required for radiographically resectable masses. The circumstances under which percutaneous or preoperative biopsy of retroperitoneal masses should be strongly considered include:

Primary tumor imaging Optimal imaging of the primary tumor depends on the anatomic site. For soft-tissue masses of the extremities, MRI has been regarded as the imaging modality of choice because it enhances the contrast between tumor and muscle and between tumor and adjacent blood vessels and also provides multiplanar definition of the lesion. However, a recent study by the Radiation Diagnostic Oncology Group that compared MRI and CT in 183 patients with malignant bone and 133 with soft-tissue tumors showed no specific advantage of MRI over CT.

For pelvic lesions, the multiplanar capability of MRI may provide superior single-modality imaging. In the retroperitoneum and abdomen, CT usually provides satisfactory anatomic definition of the lesion. Occasionally, MRI with gradient sequence imaging can better delineate the relationship of the tumor to midline vascular structures, particularly the inferior vena cava and aorta.

More invasive studies, such as angiography and cavography, are almost never required for the evaluation of soft-tissue sarcomas.

Imaging for metastatic disease Cost-effective imaging to exclude the possibility of distant metastatic disease depends on the size, grade, and anatomic location of the primary tumor. In general, patients with low-grade or intermediate-/high-grade tumors < 5 cm in diameter require only a chest x-ray for satisfactory staging of the chest. This reflects the fact that these patients are at comparatively low risk for presenting with pulmonary metastases (see box). In contrast, patients with high-grade tumors ł 5 cm in size should undergo more thorough staging of the chest by CT.

The use and yield of chest x-ray and chest CT to screen for pulmonary metastases were reviewed in 112 consecutive patients presenting with T1 primary soft-tissue sarcoma. Fewer than 1% of these patients were found to have detectable pulmonary metastases. The calculated incremental cost of screening with chest x-ray and chest CT was $2.9 million dollars per case of pulmonary metastasis detected. Thus, this staging strategy has a low overall yield and does not appear to be cost-effective (Fleming JB, Holtz D. Cantor SB, et al: Proc Am Soc Clin Oncol 17:516a[abstract], 1998).

Patients with retroperitoneal and intra-abdominal visceral sarcomas should undergo single-modality imaging of the liver to exclude the possibility of synchronous hepatic metastases. The liver is a more common site for a first metastasis from these lesions.

Treatment

Surgical resection is the cornerstone of therapy for patients with localized disease. Over the past 20 years, there has been a gradual shift in the surgical management of extremity soft-tissue sarcoma away from radical ablative surgery, such as amputation or compartment resection, and 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.

The surgical approach to soft-tissue sarcomas depends on careful preoperative staging with MRI or CT for extremity lesions and a percutaneous histologic diagnosis and assessment of 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 comprised of normal host tissue interlaced with tumor fimbriae. Conservative surgical approaches in which the plane of dissection is immediately adjacent to this pseudocapsule, such as intracapsular excision or marginal excision, are associated with prohibitive local recurrence rates of 33%-63%.

Wide local resection encompassing a rim of normal tissue around the lesion has led to improvements in local 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%. For example, in a cohort of 56 patients with primarily subcutaneous or intramuscular lesions treated with wide local excision without adjuvant radiation, 4 local recurrences were noted.

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 radiation Limb-sparing surgery employing adjuvant radiation to facilitate maximal local control has become the standard approach for large (T2) extremity soft-tissue sarcomas. In most centers, upwards of 90% of patients are treated with limb-sparing approaches. Amputation is reserved as a last resort option for local 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 included postoperative therapy with doxorubicin, cyclophosphamide, and 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 control, this ideal margin is sometimes compromised 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, these can be resected en bloc and reconstructed.

Metal clips should be placed at the margins of resection in order to facilitate radiation field planning, when and if external radiation is indicated. Drain sites should be positioned close to the wound to allow inclusion in RT fields.

Regional lymphadenectomy Given the low, 2%-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 radiographically imaged for lymphadenopathy. Clinically apparent lymphadenopathy should be treated with therapeutic lymphadenectomy.

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

In a multicenter phase II trial of limb salvage by ILP with TNF and melphalan in patients with locally advanced sarcoma, at a median follow-up of > 3 years, limb salvage was achieved in 71% of a subset of 196 patients felt to warrant investigational limb-salvage therapy. TNF-based ILP appears to be an effective option for limb salvage in patients with locally advanced extremity soft-tissue sarcoma (Eggermont AMM, Schraffordt Hoops H, Klausner JM, et al: Proc Am Soc Clin Oncol 18:535a [abstract], 1999).

The agents most commonly employed for ILP have been melphalan and tumor necrosis factor-alpha (TNF-a), with or without interferon-gamma (IFN-g [Actimmune]). The results of the largest series of ILP in patients with locally advanced extremity soft-tissue sarcoma were recently reported by Eggermont and colleagues (see top box). TNF has now been approved in Europe for ILP in patients with locally advanced, grade 2/3 soft-tissue sarcomas of the extremities.

Several studies on radiation therapy alone in the treatment of unresectable or medically inoperable soft-tissue sarcomas have reported 5-year survival rates of 25%-40% and local control rates of 30%. Local control depends largely on the size of the primary tumor. Radiation doses should be at least 65 Gy, if delivery of such doses is feasible given the tumor’s location.

Radiation therapy is always combined with surgical resection in the management of extremity soft-tissue sarcomas. The decision of whether to use with preoperative (neoadjuvant) or postoperative (adjuvant) irradiation remains controversial (see bottom box).

A phase III trial from the National Cancer Institute-Canada (NCIC) randomized patients with extremity soft-tissue sarcomas to receive either preoperative or postoperative radiotherapy. Over a 3-year period, 190 patients were accrued until the study was closed early after a planned interim analysis. Although local control, metastatic outcome, and survival were similar in both groups, the group given preoperative radiation had a significantly higher incidence of wound complications than the postoperative group (35% vs 17%). The increase in the number of wound complications with preoperative radiation should be considered in the scheduling of radiation and surgery (O’Sullivan B, Davis A, Bell R, et al: Proc Am Soc Clin Oncol 18: 535a [abstract], 1999).

Preoperative irradiation has a number of theoretical advantages: (1) Smaller radiation portals can be utilized, as the scar, hematomas, and ecchymoses do not need to be covered. (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 less relatively radioresistant hypoxic cells.

Preoperative irradiation also has several drawbacks, however. These 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, M. D. Anderson Cancer Center, and Massachusetts General Hospital demonstrated local control rates of 90% using doses of approximately 50 Gy. Survival depended on the size and grade of the primary tumor. Distant metastases were the primary pattern of failure.

Postoperative radiation A number of retrospective reports, as well as a randomized trial from the National Cancer Institute (NCI), have demonstrated that limb-sparing surgery plus postoperative irradiation produces comparable local control rates to those achieved with amputation. Five-year local control rates of 70%-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, thus, adjuvant external-beam radiation should be considered in all patients with extremity sarcoma with positive or close microscopic margins, in whom reexcision is impractical. Postoperative doses of 60-65 Gy should be used.

Interstitial therapy with iridium-192 is used at some institutions as a radiation boost to the tumor bed following adjuvant external-beam irradiation. At Memorial Sloan-Kettering, 89% of patients randomized to adjuvant brachytherapy achieved local control, as compared with only 66% of those who had surgery alone. If an implant alone is used, the dose is 40-45 Gy to a volume that includes all margins; when a boost is combined with additional external-beam radiation, a dose of 20-25 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 must be done with caution and with strict attention to the incision site.

Comparison of radiation techniques Comparable local control results (90%) are obtained with preoperative, postoperative, and interstitial techniques, although rates of wound complications are higher with preoperative techniques (see box ).

Brachytherapy can offer a number of advantages for the patient: When brachytherapy is employed as the sole adjuvant, the patient’s entire treatment (surgery and radiation) is completed in a 10- to 12-day period, compared with the 10-12 weeks required for typical external-beam radiation (6-7 weeks) and surgery (4- to 6-week break before or after radiation). 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.

Regardless of the technique employed, local control is a highly achievable and a worthwhile end point, as demonstrated in a study of 911 patients treated by various techniques at Memorial Sloan-Kettering. Of the 116 patients who developed a local recurrence, 38 subsequently developed metastases and 34 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 extremity sarcomas and larger (ł 5 cm) low-grade lesions. If low-grade, small lesions can be resected with clear margins, radiotherapy can be omitted. Postoperative therapy with either external-beam radiation (with or without an interstitial implant boost) or an implant alone will achieve a high likelihood of local control and, therefore, limb preservation. Preoperative radiation, although equally efficacious, does carry a higher wound complication rate (see box).

Only 50% of patients with retroperitoneal sarcoma are able to undergo complete surgical resection. Of patients undergoing complete resection, one-half develop a 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 in the treatment of 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 in determining the indications for radiation therapy.

Postoperative radiation Two-year local control rates of 70% have been reported with the addition of postoperative irradiation. However, radiation of the retroperitoneum/abdomen in doses that have effected local control in extremity soft-tissue sarcoma (50-65 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 > 10-15 cm, the radiation fields employed are generally also quite large. 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.

Intraoperative radiation In a prospective trial from the NCI, 35 patients with completely resected retroperitoneal sarcomas were randomized to receive either intraoperative electron-beam radiation (IORT) followed by low-dose (30-40 Gy) postoperative external-beam radiation or high-dose postoperative external-beam radiation (35-40 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.

A similar suggestion of improved local control was reported in a smaller nonrandomized series from Massachusetts General Hospital. Although these local control results are encouraging, IORT remains investigational and cannot be advocated on a routine basis at this time.

The striking success of combined-modality therapy in children with osteogenic sarcoma, embryonal rhabdomyosarcoma, and the Ewing’s sarcoma family of tumors, including primitive (or peripheral) neuroectodermal tumor (PNET), has provided the stimulus for the use of aggressive combined-modality approaches in adult patients. Unfortunately, systemic chemotherapy appears to be less effective in patients with adult-type sarcoma.

Doxorubicin (Adriamycin and others) and ifosfamide (Ifex) are the most active antineoplastic drugs; in large trials, each yields major objective responses in 17%-20% of patients. In Europe, epirubicin, a doxorubicin analog, is often used instead of doxorubicin. Dacarbazine (DTIC) has also demonstrated antitumor activity but is used most commonly in combination chemotherapy regimens.

The literature is replete with reports of the apparent benefit of combined-modality therapy in patients with resectable soft-tissue sarcoma. Most series are either retrospective or small, nonrandomized trials. Thirteen published trials have compared postoperative chemotherapy to observation alone in adult patients 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 sarcoma. In some trials, patient ineligibility rates were as high as 20%, and in none of these trials 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 of cyclophosphamide, vincristine, Adriamycin, and DTIC (CyVADIC). A significant survival advantage was seen only in one combination chemotherapy trial.

Nonetheless, some of the trials showed a trend toward improved disease-free survival or a statistically significant improvement in this end point in patients given adjuvant chemotherapy, especially among those with high-grade extremity sarcoma. Analyses of the pooled results of the published literature are consistent with this observation.

SMAC meta-analysis A formal meta-analysis of individual data from 1,568 patients who participated in the 13 published trials (plus one additional unpublished trial) has been performed by the Sarcoma Meta-Analysis Collaboration (SMAC). 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 for distant relapse–free survival was 0.70; ie, the risk of distant relapse (metastasis) was reduced by 30% in treated patients. The absolute benefit at 10 years was 10%, so that the recurrence-free survival rate at 10 years was improved from 60% to 70%. Also, the hazard ratio for local recurrence–free survival was 0.73 (27% reduction in the risk of local recurrence), and the absolute benefit was 6%.

The hazard ratio for overall survival, however, was 0.89, which did not meet the criteria for statistical significance. In absolute terms, there was a possible improvement in survival from 50% to 54% at 10 years. 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 extremity sarcoma.

Ifosfamide-containing trials Only one trial included in the meta-analysis 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.

The Italian Sarcoma Group conducted a trial in which patients 18-65 years old with high-grade extremity sarcoma > 5 cm were randomized to either postoperative chemotherapy with 5 cycles of epirubicin (60 mg/m˛ on days 1 and 2) plus ifosfamide (1.8 g/m˛ on days 1-5) given with granulocyte colony stimulating factor (G-CSF, filgrastim [Neupogen]) every 3 weeks, or observation alone. The trial had been planned for 200 patients, but was interrupted after accrual of 104 patients when an interim analysis showed a significant survival advantage for the chemotherapy-treated group. With a minimum follow-up of 36 months, a statistically significant advantage was still evident in chemotherapy-treated patients with respect to overall survival (P = .01), disease-free survival, freedom from local recurrence, and freedom from distant metastasis.

Preoperative chemotherapy has been adopted at many centers for patients with large high-grade sarcoma, especially those of the extremity. Other centers favor alternating chemotherapy and radiation.

Aside from theoretical 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. Finally, it has been suggested that response to preoperative therapy may provide important prognostic information, although this remains controversial.

Thus, the superiority of preoperative chemotherapy remains speculative. In fact, the European Organization for Research and Treatment of Cancer (EORTC) is conducting a prospective, randomized trial in which patients are randomized to receive or not to receive preoperative therapy.

Despite optimal multimodality therapy, local recurrence develops in 10%-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 retroperitoneal and head and neck sarcomas, for which adequate surgical margins are difficult to attain. In addition, high-dose adjuvant radiation 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% range typically seen for extremity sarcomas.

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

Adjuvant radiation therapy If no prior radiation therapy was employed, adjuvant radiation (50-65 Gy) should be used after surgery for locally recurrent disease. Radiation therapy (external-beam radiation or brachytherapy) should be considered in patients for whom previous radiation doses were subtherapeutic or previous radiation field design permits additional treatment.

Patients who develop local recurrence following previous full-dose radiation represent a difficult local control challenge. A report from Memorial Sloan-Kettering suggests that limb-sparing surgery combined with adjuvant brachytherapy may produce excellent local control and function in this group.

ILP Ongoing clinical investigations are defining the role of ILP in the management of patients with locally recurrent sarcoma.

Thoracotomy and metastectomy The most common site of metastatic disease involvement of soft-tissue sarcoma is the lung. Rates of 3-year survival following thoracotomy for pulmonary metastasectomy ranges 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 a thoracotomy; and (4) complete resection of all disease appears to be possible.

Preresection chemotherapy Chemotherapy is often recommended before resection of lung metastases. Yet, there are no convincing data to support this approach. Indeed, the EORTC is conducting a prospective, randomized trial specifically to examine this issue.

Doxorubicin Early trials of doxorubicin reported major responses in ~30% of patients with advanced soft-tissue sarcoma. In more recent randomized series, however, the rate of responses has been closer to 17%.

Subset analysis of patients with soft-tissue sarcoma from a broad phase II trial in which patients were randomized to receive various doses of doxorubicin demonstrated a steep dose-response relationship; patients treated with doses < 60 mg/m˛ rarely responded. Whether dose-intensification of doxorubicin is associated with improved survival remains an open question (see below).

It had been hoped that liposomal doxorubicin (Doxil) might be at least as efficacious as standard doxorubicin, with less cardiac toxicity. Although responses to the liposomal formulation have been seen in patients with soft-tissue sarcoma, most phase II trials have not demonstrated sufficiently promising activity at the doses and schedules tested.

Ifosfamide In a randomized phase II trial conducted by the EORTC, 18% of patients treated with ifosfamide (5 g/m˛) experienced major responses, in contrast to 12% of patients treated with cyclophosphamide (1.5 g/m˛, despite the greater myelosuppression with the latter agent. In a large American phase II trial, 17 of 99 patients with soft-tissue sarcoma responded to ifosfamide (8 g/m˛), all of the patients had been treated previously with doxorubicin-based therapy, suggesting a degree of non-cross-resistance.

Increasing ifosfamide dose Recent trials have focused on increasing the dose of ifosfamide. Responses to ifosfamide (ł 12 g/m˛) have been observed in patients who progressed while receiving lower doses, supporting the concept of a dose-response relationship.

In a randomized trial, the response to 9 g/m˛ of ifosfamide (17.5%) was superior to the 3% response observed among patients treated with 5 g/m˛. The reason for the low response to the lower dose was unclear. In a subsequent trial by the same investigators, the response to 12 g/m˛ was only 14%, however.

Among 45 “assessable” patients enrolled in a Spanish phase II trial of ifosfamide (14 g/m˛ given by continuous infusion over 6 days), the response rate was 37.7%, but 47% of patients developed febrile neutropenia and 32%, grade 3 neurotoxicity.

At M. D. Anderson, ifosfamide (14 g/m˛ given by continuous infusion over 3 days) yielded responses in 29% of 37 patients with soft-tissue sarcoma, and 40% of patients with bone sarcoma. Also within that report was a small cohort of patients in whom the response to the same total dose of ifosfamide was higher when the drug was given by an intermittent bolus rather than a continuous infusion; this led the authors to suggest that bolus therapy is more efficacious than continuous infusion. Pharmacokinetic studies, however, have shown no difference between a 1-hour infusion or bolus injection of ifosfamide with respect to the area under the curve for serum ifosfamide or its metabolites, or the levels of ifosfamide metabolites in urine.

Ifosfamide doses as high as 14-20 g/m˛ have been given with hematopoietic growth factor support; reported response rates are high, but neurologic and renal toxicity often are dose-limiting.

DTIC The activity of DTIC in soft-tissue sarcoma has been recognized since the 1970s, and was confirmed in a formal phase II trial. This marginally active agent has been used mostly in doxorubicin-based combinations.

Other agents, including the taxanes, gemcitabine (Gemzar), vinca alkaloids, and platinum compounds, have demonstrated only marginal activity in phase II trials.

Combination chemotherapy regimens have been used widely in the management of patients with soft-tissue sarcoma. High response rates have been reported in a number of single-arm phase II trials. Most combination regimens include an anthracycline (either doxorubicin or epirubicin) plus an alkylating agent, DTIC, or both agents. Overall, response rates are higher in these single-arm trials than rates observed when the same regimens are tested in larger, randomized studies.

AD and CyVADIC regimens The combination of Adriamycin plus DTIC (AD regimen) has been studied extensively. Also, for over a decade, the CyVADIC regimen was widely accepted as the standard of care. In a prospective, randomized trial, however, CyVADIC did not prove to be superior to doxorubicin alone.

Doxorubicin (or epirubicin) plus ifosfamide Combinations of doxorubicin (or epirubicin) plus ifosfamide consistently have yielded responses in over 25% of patients in single-arm trials. In sequential trials conducted by the EORTC, doxorubicin (75 mg/m2) plus ifosfamide (5 g/m˛) was superior to doxorubicin (50 mg/m˛) plus ifosfamide (5 g/m˛). However, a prospective, randomized trial comparing the two regimens found no difference in response rate or survival.

MAID regimen The MAID regimen (mesna, Adriamycin [60 mg/m˛], ifosfamide [7.5 g/m˛], and DTIC [900 mg/m˛], all given over 3 days) yielded an overall response rate in 47% of patients in a large phase II trial. In a randomized comparison of AD vs MAID, the response to MAID was 32%, compared to a 17% response with the two-drug regimen (P < .002). However, the price paid for the higher response was toxicity; of eight toxic deaths reported in this trial, seven occurred among the 170 patients treated with MAID. All treatment-related deaths occurred in patients > 50 years old. During the study, the doses of MAID were reduced to lessen toxicity. Median survival did not differ significantly between the two regimens, although a trend favoring the AD regimen was noted.

In a randomized trial from France, a 25% escalation in the doses of MAID did not improve outcome.

Combination chemotherapy vs single-agent doxorubicin Combination chemotherapy has been compared with single-agent doxorubicin in eight randomized phase III trials. Two trials were limited to patients with uterine sarcoma. Some of these studies showed superior response rates with combination chemotherapy, but none of the trials found a significant survival advantage. Kaplan-Meier plots of survival are virtually superimposable within each trial, and from trial to trial.

It should be emphasized that approximately 20%-25% of patients entered into such trials are alive 2 years after therapy is initiated. Complete responses are uncommon and do not appear to translate into prolonged survival.

Intensifying chemotherapy Hematopoietic growth factors have facilitated the evaluation of dose-intensive chemotherapy in patients with sarcoma. The nonhematologic toxicities (cardiac, neurologic, and renal) of the agents most active in soft-tissue sarcoma prevent dramatic dose escalation.

Phase I and II trials of dose-intense anthracycline/ifosfamide regimens with hematopoietic growth factor support have shown that doxorubicin (79-90 mg/m˛) can be used in combination with ifosfamide (10-12 g/m˛) in selected patients. Response rates as high as 69% have been reported. Although toxicity increases, often dramatically, with these relatively modest dose escalations, the clinical benefit in terms of survival or palliation in patients with metastatic disease remains uncertain.

No randomized trial has demonstrated a survival advantage for patients treated with these more aggressive regimens. In one randomized trial, however, the French Federation of Cancer Centers demonstrated that, in comparison with standard doses, a 25% escalation in doses of MAID with G-CSF support did not improve outcome.

High-dose therapy with autologous stem-cell or marrow rescue There is limited experience using high-dose chemotherapy with autologous stem-cell or marrow rescue in adults with soft-tissue sarcoma. The results to date do not suggest that this approach is likely to dramatically increase survival.

Prognostic factors for response to therapy Over the past 20 years, the EORTC has collected data on more than 2,000 patients with metastatic disease who participated in first-line anthracycline-based chemotherapy trials. Multivariate analysis of this data set indicated that the patients most likely to respond to chemotherapy are patients without liver metastases (P < .0001), younger patients, individuals with high histologic grade, and those with liposarcoma. In this Cox model, the factors associated with superior survival were good performance status, absence of liver metastases, low histologic grade, a long time to metastasis after treatment of the primary, and young age.

More recently, these same investigators have reported that the observed response rate is superior in patients who have lung metastases only, as compared with those who have metastases to the lung and other sites, or to other sites only. These findings highlight the danger of reaching broad conclusions based on extrapolations from small trials that include highly selected patients. The EORTC data are also consistent with the observation that patients with metastatic GI sarcoma rarely respond to standard chemotherapy regimens. This increasingly recognized observation has been used to explain the low response rates seen in some trials.