Soft-Tissue Sarcomas

Chemotherapy for Unresectable Locally Advanced or Metastatic Disease

Single agents

Doxorubicin. Early trials of doxorubicin(Drug information on doxorubicin) reported major responses in approximately 30% of patients with advanced soft-tissue sarcoma. In more recent randomized series, however, the rate of response has been closer to 15%.

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 below 60 mg/m² rarely responded. Whether dose intensification of doxorubicin is associated with improved survival remains an open question (see section on "Intensifying chemotherapy").

Pegylated liposomal doxorubicin (Doxil in the United States, Caelyx in Europe) has demonstrated limited activity in phase II trials, especially in patients whose disease is refractory to standard doxorubicin. In a randomized comparison among 95 previously untreated patients, however, the response rates to pegylated liposomal doxorubicin (50 mg/m² every 4 weeks; 10%) and to standard doxorubicin (75 mg/m² every 3 weeks; 9%) were similar, with no significant difference in time to disease progression or survival. Response rates improved to 14% and 12%, respectively, when GIST cases were excluded.

Ifosfamide. In a randomized phase II trial conducted by EORTC, 18% of patients treated with ifosfamide (5 g/m²) experienced major responses, in contrast to 12% of patients treated with cyclophosphamide(Drug information on cyclophosphamide) (1.5 g/m²), 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(Drug information on ifosfamide) (8 g/m²). All of the patients had been treated previously with doxorubicin-based therapy, suggesting a degree of non–cross-resistance.

• Increasing ifosfamide dose— Responses to ifosfamide (≥ 12 g/m²) have been observed in patients whose disease progressed while receiving lower doses, supporting the concept of a dose-response relationship.

In a randomized trial, the response to 9 g/m² of ifosfamide (17.5%) was superior to the 3% response observed among patients treated with 5 g/m². 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/m² was only 14%, however.

Among 45 evaluable patients enrolled in a Spanish phase II trial of ifosfamide (given by continuous infusion over 6 days), the response rate was 38%, but 47% of patients developed febrile neutropenia and 32% had grade 3 neurotoxicity.

At MD Anderson Cancer Center, ifosfamide (14 g/m² given by continuous infusion over 3 days) yielded responses in 29% of 37 patients with soft-tissue sarcoma and 40% of 37 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 finding 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 and bolus injection of ifosfamide with respect to the area under the concentration-time curve (AUC) for serum ifosfamide or its metabolites or the levels of ifosfamide metabolites in urine.

In an EORTC phase II trial, ifosfamide (12 g/m² given as a 3-day continuous infusion every 4 weeks) yielded a response rate of 17% among 89 chemotherapy-naive patients and of 16% among 25 previously treated patients.

Ifosfamide doses as high as 14 to 20 g/m² have been given with hematopoietic growth factor support; reported response rates are high, but neurologic and renal toxicities often are dose-limiting. The available data suggest that synovial sarcoma is particularly sensitive to ifosfamide.

Dacarbazine. The activity of dacarbazine(Drug information on dacarbazine) 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. In particular, patients with leiomyosarcoma respond better to dacarbazine than do patients with other sarcoma subtypes.

Ecteinascidin. Ecteinascidin (ET-743, trabectedin), a novel compound derived from a marine organism, has demonstrated promising activity as well. In phase I trials, trabectedin demonstrated activity in heavily pretreated patients with advanced sarcoma. Three phase II trials of trabectedin (1,500 mg/m² over 24 hours every 3 weeks) in refractory non-GIST soft-tissue sarcoma have been reported.

On the basis of randomized phase II data, ecteinascidin (Yondelis) was approved in Europe for use in refractory soft tissue sarcomas, but has not been approved in the United States. Myxoid/round cell liposarcoma appears to be the subtype with greatest sensitivity to this novel agent. Care must be taken in its administration to follow liver function tests, which predict for rhabdomyolysis and death if appropriate dose reductions are not made.

TABLE 4Chemotherapy regimens for soft-tissue sarcoma

Other agents. Gemcitabine(Drug information on gemcitabine) (Gemzar) has demonstrated modest activity in several phase II trials, although results of a recent Southwest Oncology Group (SWOG) trial were disappointing. Taxanes, vinca alkaloids, and platinum compounds have demonstrated only marginal activity, however. It should be noted that the taxanes, gemcitabine, and vinorelbine (Navelbine) have been observed to be active in angiosarcoma, especially cases involving the scalp and face.

Combination chemotherapy

Combination chemotherapy regimens have been used widely in the management of patients with soft-tissue sarcoma (Table 4). 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(Drug information on epirubicin)) plus an alkylating agent, dacarbazine, or both agents. Overall response rates are higher in these single-arm trials than when the same regimens are tested in larger, randomized studies.

CyVADIC and doxorubicin/dacarbazine regimens. Combinations of doxorubicin with other agents have not proved to be superior to doxorubicin alone in terms of overall survival. Also, for over a decade, the CyVADIC regimen was widely accepted as the standard of care. In a prospective, randomized trial, however, CyVADIC was not superior to doxorubicin alone.

Doxorubicin (or epirubicin) plus ifosfamide. Combinations of doxorubicin (or epirubicin) plus ifosfamide have consistently yielded responses in over 25% of patients in single-arm trials. In sequential trials conducted by the EORTC, doxorubicin at 75 mg/m² plus ifosfamide (5 g/m²) was superior to doxorubicin at 50 mg/m² plus ifosfamide (5 g/m²). A prospective randomized EORTC trial with 314 patients compared the two regimens. There was no difference in response rate or overall survival, but disease progression-free survival favored the more intensive regimen.

The strategy of intensifying the dosing of ifosfamide within the context of combination chemotherapy was explored in a randomized phase II trial. This study included patients with localized disease treated with four cycles of preoperative chemotherapy as well as patients with metastatic disease. Overall, there was no survival benefit for patients treated with doxorubicin (60 mg/m²) plus 12 g/m² of ifosfamide over those treated with doxorubicin (60 mg/m²) plus 6 g/m² of ifosfamide. Also, there was no advantage to the patients with localized disease in terms of disease-free survival.

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. A meta-analysis confirmed the higher response rate when ifosfamide is added to other agents and showed no benefit at 1 year of combination therapy over single agents, likely due to the lack of synergy between anthracyclines and ifosfamide. Patients can achieve equal benefit by sequential use of such agents rather than by combinations.

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

Gemcitabine plus docetaxel. In a phase II study of 34 patients with unresectable leiomyosarcoma, mostly uterine in origin, 53% responded to a combination of gemcitabine (given by 90-minute infusion) plus docetaxel (Taxotere), with G-CSF support. An additional 20% had stable disease. Almost half of the patients had disease progression after anthracycline-based therapy. The median time to disease progression was 5.6 months, and grade 3 or 4 toxicity was uncommon. The activity of the gemcitabine-docetaxel combination was confirmed in a variety of other sarcoma subtypes in another study, which also confirmed the rationale for the sequence used in the study in vitro. Conversely, gemcitabine-docetaxel was examined in the adjuvant setting, in a phase II study, with no evidence of long-term benefit over historical controls.

A prospective, randomized trial comparing gemcitabine-docetaxel with gemcitabine alone in a spectrum of histologic types of sarcoma has been completed. The response rates were 8% for gemcitabine alone and 16% for gemcitabine-docetaxel. Time to disease progression and overall survival were superior with gemcitabine-docetaxel (17.9 months vs 11 months). Although this is one of the few studies in metastatic sarcoma to show a survival advantage, enthusiasm is tempered by toxicity, causing treatment discontinuation in up to 50% of patients after 6 months of gemcitabine-docetaxel chemotherapy. These data suggest that a dose reduction, of the docetaxel in particular, is needed in the off-study use of the therapy.

In the authors' experience, weekly administration of lower doses of each agent is more tolerable than the large day-8 dose of docetaxel and remains an active regimen. The randomized study previously noted that the response rate was higher in patients with high-grade undifferentiated pleomorphic sarcoma (UPS, formerly termed MFH [malignant fibrous histiocytoma]) than in patients with leiomyosarcoma.

Gemcitabine plus vinorelbine. These agents given together were also active in one phase II study. It is not clear whether either vinorelbine or docetaxel is synergistic for all histologies tested or synergy is only observed for specific subtypes.

Kinase-targeted agents in non-GIST sarcomas. Several of the commercially available tyrosine kinase inhibitors have been examined for activity in the setting of metastatic disease. In general, response rates have been low.

Exceptions to this statement may include a 15% response rate of patients with synovial sarcoma to pazopanib (Votrient), a 14% response rate of patients with angiosarcoma to sorafenib (Nexavar) (particularly those induced by therapeutic radiation) and similar activity of bevacizumab (Avastin) in angiosarcomas, and reports of the utility of imatinib(Drug information on imatinib) in patients with the rare sarcoma subtype dermatofibrosarcoma protuberans. There appears to be at least modest activity of sunitinib (Sutent) in alveolar soft-part sarcoma, clear-cell sarcoma, and solitary fibrous tumor/hemangiopericytoma, and of cediranib (Recentin) in patients with metastatic alveolar soft-part sarcoma.

Activity of pazopanib was confirmed in a randomized phase III study reported by van der Graaf et al, comparing placebo to pazopanib at 800 mg orally daily. Median progression-free survival was 20 weeks, compared with 7 weeks on placebo. This degree of activity appears to be greater than that of maintenance use of an mTOR inhibitor, ridaforolimus, which improved time to progression by 3.1 weeks vs placebo in patients with a response or stable disease after cytotoxic chemotherapy. These findings have led to regulatory approval of pazopanib for soft tissue sarcomas other than liposarcoma or GIST that have gotten worse despite prior therapy, while ridaforolimus was not granted regulatory approval.

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/II trials of dose-intense anthracycline/ifosfamide regimens with hematopoietic growth factor support have shown that doxorubicin (70 to 90 mg/m²) can be used in combination with ifosfamide (10 to 12 g/m²) 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 Sarcoma Group (FFCCSG) demonstrated that, in comparison with standard doses, a 25% escalation in doses of doxorubicin, ifosfamide, and dacarbazine with G-CSF support did not improve outcome.

High-dose therapy with autologous stem-cell transplantation. Most trials are small and presumably involve highly selected patients. In one trial involving 30 patients with metastatic or locally advanced sarcoma accrued over 6 years, more than 20% were free of disease progression at 5 years after high-dose therapy with stem-cell rescue. Complete response to standard induction chemotherapy predicted superior 5-year survival. Based on these favorable results, the investigators suggested a prospective randomized trial examining this approach. Although some groups are still exploring this approach, the appropriateness of generalizing these results to most patients with soft-tissue sarcoma remains speculative. In Ewing sarcoma, the results of the Euro-EWING 99 study indicate there may be benefit from high-dose therapy with stem cell support for people with limited metastatic disease at presentation, though these data are not randomized.

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 these data indicated that the patients most likely to respond to chemotherapy are those 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 tumor, and young age.

More recently, these same investigators have reported that the observed response rate is superior in patients who have pulmonary metastases only, as compared with those who have metastases to the lungs 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 GIST rarely respond to standard chemotherapy regimens. This increasingly recognized observation has been used to explain the low response rates seen in some trials.

Targeted therapy for GISTs

Advances in our understanding of the biology of GIST, and the availability of an effective therapy for patients with advanced disease, have resulted in intense interest in this entity and rapid expansion of diagnosis of this disease. Because this entity had not been recognized, the incidence of GIST was underappreciated. GIST is the most common nonepithelial tumor of the GI tract, with an estimated annual incidence of 3,000 to 3,500 cases in the United States. Approximately 50% to 60% of GISTs arise in the stomach and 25% in the small bowel. Other sites include the rest of the GI tract, the omentum, mesentery, and retroperitoneum. These tumors may range in size from millimeters to huge masses. It is not clear how many of these GISTs become clinically relevant and how many are noted incidentally at the time of endoscopic ultrasonography or other abdominal procedures.

The demonstration of the efficacy of imatinib in GIST has been among the most dramatic and exciting observations in solid-tumor oncology. A randomized multicenter trial evaluated two doses of oral imatinib (400 vs 600 mg) in 147 patients with advanced GISTs; 54% had a partial response and 28% had stable disease. Response was sustained, and with these and other data it is clear that patients do not progress for 2 years or more on average on imatinib. Most patients had mild grade 1 or 2 toxicity, but only 21% had severe grade 3 or 4 toxicity. GI or intra-abdominal hemorrhage occurred in 5% of patients. There was no difference in response or toxicity between the two doses.

These observations were expanded in two parallel, multi-institution trials in which patients with GISTs were randomized to receive imatinib (400 or 800 mg daily). The results were very similar. In the American trial, among 746 registered patients, the overall response rate was 43% for patients treated with 400 mg and 41% for those treated with 800 mg. There were no differences in survival between the two arms. At 2 years, progression-free and overall survival rates in the 400-mg arm were 50% and 78%, respectively. In the 800-mg arm, the rate of progression-free survival at 2 years was 53%, and the rate of overall survival was 73%.

In a large European-Australasian trial, 946 patients were randomized to receive imatinib (400 mg daily or twice a day). Among the 615 patients whose response could be evaluated, there was no difference in response frequency (43%) or survival between the two arms. Complete responses were seen in 3% and 2% of the lower-dose and higher-dose patients, respectively. Sixty-nine percent of patients whose disease was progressing on 400 mg of imatinib were allowed to cross over to the higher dose (800 mg). Further therapeutic activity was seen, with 26% of these patients free of disease progression at 1 year.

Based on these results, the European Organisation for Research and Treatment of Cancer (EORTC), in conjunction with the Italian Sarcoma Group (ISG) and the Australasian Gastrointestinal Group (AGG), has reported its results to further identify factors predicting early and late resistance to imatinib in patients with GIST. Initial resistance was defined as disease progression within 3 months of randomization, and late resistance was disease progression beyond 3 months. Initial resistance was noted in 116 of 934 patients (12%). Low hemoglobin level, high granulocyte count, presence of lung metastases, and the absence of liver metastases were independent predictors of initial resistance. Late resistance occurred in 347 of 818 patients. Independent predictors were high baseline granulocyte count, primary tumor outside the stomach, large tumor size, and low initial imatinib dose. The impact of the dose on late resistance was significant in patients with high baseline granulocyte counts and in patients with GI tumors originating outside the stomach and small intestine.

Among a group of 127 patients with advanced GISTs, activating mutations of KIT or PDGFRA were identified in 87.4% and 3.9% of patients, respectively. In patients harboring an exon 11 mutation of KIT, the partial remission rate was 83.5%, whereas in patients without a discernible mutation in KIT or PDGFRA, the partial remission rate was 9.1%. The presence of an exon 11 mutation in KIT correlated with clinical response, decreased risk of treatment failure, and improved overall survival.

A GIST Task Force was impaneled to develop guidelines for the evaluation and treatment of patients with GIST. This group recommended 400 mg daily as the initial starting dose of imatinib. Dose escalation should be considered in patients who do not respond initially or who demonstrate unequivocal disease progression. Surgery remains the primary modality for treatment of primary GIST, and adjuvant imatinib has been approved for use in Europe and the United States on the basis of a large randomized clinical trial.

Sunitinib is an active agent in imatinib-refractory GIST. In both phase I/II and III studies, the response rate is on the order of 10%, with a greater than 60% chance of these patients remaining on treatment for 6 months or longer. Notably, the benefit was greatest in patients with the converse KIT genetic phenotype (exon 9 mutation or wild type KIT) to those who were sensitive to imatinib (exon 11 mutation). Nonetheless, imatinib remains the first line of therapy regardless of mutation type, because there is still a response rate seen for imatinib in patients with wild-type or exon 9 KIT mutations and because imatinib is less toxic than sunitinib in its present schedule (4 weeks on at 50 mg oral daily, 2 weeks off). Some studies are examining alternative schedules of sunitinib (eg, 37.5 mg oral daily continuously), whereas other studies are evaluating the benefit of other small-molecule inhibitors of KIT. Newer tyrosine kinase inhibitors such as sorafenib may have some activity in the imatinib- and sunitinib-refractory settings. A phase III study of Hsp90 (heat shock protein 90) inhibitor vs placebo for kinase inhibitor-resistant GIST was closed due to deaths observed on study.

The French Sarcoma Group (FSG) conducted a phase III randomized trial evaluating intermittent vs continuous imatinib therapy after completion of 1 year of continuous imatinib therapy. A total of 159 patients have enrolled in the trial. A partial or complete response was achieved in 52% of patients. Twenty-three patients were randomized to join the intermittent arm, and 23 the continuous arm. After 3 months, five patients (21%) in the intermittent arm had evidence of disease progression, vs no patients in the continuous arm. Reintroduction of imatinib resulted in tumor control in all patients.

Assessment of response and treatment after disease progression on imatinib. The use of standard (RECIST) response criteria in patients with GIST may be misleading. On CT or MR imaging, large tumor masses may become completely necrotic without a reduction in size for months in spite of dramatic clinical improvement. Indeed, such masses may actually increase in size. ¹⁸F-FDG (¹⁸F-fluorodeoxyglucose)–PET imaging may be useful in selected patients, as response may be seen as early as 24 hours after a dose of imatinib. However, in general, with the understanding that loss of tumor vascularity represents a good radiological result, very little is to be gained with the use of PET vs IV contrast-enhanced CT scan or MRI. In patients who cannot have IV CT or MRI contrast, PET may provide an alternate means of following treatment efficacy over time. It should be noted that the survival of patients with stable disease parallels that of patients with major objective responses using RECIST criteria.

Surgery does not cure GIST that recurs after resection of primary disease and should be managed as metastatic disease. However, multimodality therapy should be considered in patients with limited sites of disease. It has also been recognized that patients with disease progression in limited sites of disease, occasionally having a growing nodule within a previously necrotic metastasis, may experience rapid disease progression of previously controlled areas. Thus, imatinib should be continued indefinitely in such patients, who should be referred for investigational therapy.

US Food and Drug Administration (FDA)-approved therapy for metastatic disease includes imatinib in first-line and sunitinib in second-line treatment. If there is disease progression on second-line sunitinib, patients may be able to receive another kinase inhibitor such as sorafenib, which has activity in GIST. A phase III study of another second-generation anti-KIT drug, nilotinib (Tasigna), was closed for lack of efficacy.

Sidebar: Given the activity of sorafenib (Nexavar) in sunitinib (Sutent)-refractory gastrointestinal stromal tumor (GIST), a phase III study was performed to test regorafenib (sorafenib with an extra fluorine atom) in a double-blind placebo controlled study. This study had a crossover design, so a survival advantage was neither anticipated nor observed. Progression-free survival was significantly better on regorafenib vs placebo (4.8 months vs 0.9 months; HR = 0.27; P < .0001). As a result, regorafenib is a new third-line standard of care for metastatic GIST (Demetri GD et al: J Clin Oncol 30[suppl]: Abstr LBA10008 2012).

Adjuvant Imatinib for GIST

The American College of Surgeons Oncology Group (ACOSOG) phase III study of adjuvant imatinib examined imatinib for 48 weeks vs placebo. The study assessed patients with any GIST of at least 3 cm in maximum dimension. DeMatteo et al indicated that there was only a 3% chance of disease progression after the 48 weeks of therapy, in comparison to 17% in those who underwent surgery alone. However, there was a decay in the progression-free survival curve after approximately 2 to 2.5 years of therapy to that of the untreated patients. Furthermore, overall survival was no different between the two study arms, although median survival was only 15 months at the time of the report. These data indicate that although imatinib is a good salvage strategy for patients with recurrent GIST, it cannot be considered a new standard of care for all patients, given the lack of overall survival benefit noted with evidence of disease progression after therapy is complete. Further follow-up research to assess the potential use of adjuvant imatinib based on mutation status has been reported in preliminary form at the 2010 meeting of the American Society of Clinical Oncology (ASCO). In the ASCO presentation by Corless et al, there was no improvement in overall survival with adjuvant imatinib, since relapsing patients so frequently responded to imatinib in the metastatic setting. Furthermore, there were certain mutational subtypes in which it was clear that 400 mg orally per day for 48 weeks did not improve progression-free survival over placebo, including patients with exon 9 mutations in KIT, so-called wild type GIST, and patients with PDGFRA mutation D842V. Thus, if adjuvant therapy is to be given, patients with the more common exon 11 KIT mutations (or the rare PDGFRA mutant non-D842V) could be considered for therapy.

Sidebar: One of the follow-up studies to Z9001 study was the Scandinavian Sarcoma Group (SSG) XVII study, examining 1 year vs 3 years of imatinib (Gleevec) for intermediate- to high-risk gastrointestinal stromal tumor (GIST). This study showed for the first time not only a progression-free survival advantage to the shorter course of therapy but also an overall survival advantage for longer exposure to imatinib (92% vs 82% 5-year survival). As a result, 3 years of imatinib is the present standard of care for high-risk GIST (Joensuu H et al: JAMA 307:1265-1272, 2012).

Recommendations for the treatment of metastatic sarcoma

• For patients with rapidly progressive disease or with symptoms, combination chemotherapy with an anthracycline/ifosfamide combination is indicated. For most patients, however, sequential single-agent therapy is less toxic and not inferior in terms of survival.

• The management of metastatic GIST involves imatinib as first-line therapy, and increasing doses of imatinib, when feasible, before changing to sunitinib. Some patients can be maintained with good responses to imatinib for more than 5 years.

• Regorafenib is a third-line option for metastatic GIST after failure of prior therapy.

• Schedules other than the 50 mg oral daily dose of sunitinib (4 weeks on, 2 off) can be considered in an attempt to minimize the drug's toxicity (eg, 25 to 37.5 mg orally per day, without interruption).

• Three years of adjuvant imatinib is a good standard of care for higher-risk GIST and is associated with a survival advantage. A simple rule of thumb regarding high-risk patients includes the rule of fives. High-risk tumors include gastric GISTs that are both 5 cm or more in size with at least five mitoses per 50 high-powered fields, and GIST from other sites are higher risk if they are either 5 cm or more in size or have at least five mitoses per 50 high-powered fields.

• Surgery is increasingly being performed at the time of best response (typically 6 to 9 months) and at the time of limited disease progression. There are no data that indicate that early surgery (at the time of best response) leads to superior survival than later surgery (at the time of limited disease progression). Surgery should generally be avoided in patients with multifocal progressive disease; a change in medical therapy is appropriate in this setting.

• The importance of histology relevant to selection of therapy is increasingly being appreciated. It is especially significant to distinguish GISTs from GI leiomyosarcomas. Patients with GIST that is progressive on standard therapy should be referred to subspecialty centers experienced in the multimodality management of this disease. Data regarding kinase-targeted agents will likely lead to the use of such agents for a limited number of rare sarcoma subtypes.

• Periods of watchful waiting may be appropriate for many patients with metastatic sarcoma who have no or only minimal symptoms.