Editor(s): Peter W. T. Pisters, M.D. Reviewers: Murray F. Brennan, M.D., Burton L. Eisenberg, M.D., Harald J. Hoekstra, M.D., William G. Kraybill, M.D., Frits van Coevorden, M.D., Shreyaskumar R. Patel, M.D., Vernon K. Sondak, M.D.

General Reviews

Pisters PWT, Brennan MF. Sarcomas of Soft Tissue. In Abeloff M, Armitage J, Lichter A, Niederhuber J (eds). Clinical Oncology. New York, NY: Churchill Livingstone; 1999:2273-2313.

Pisters PWT, Demetri G, O'Sullivan B. Sarcomas of Nonosseous Tissues. In: Holland JF, Bast RC Jr, Pollock RE, Frei E III, Kufe DW, Weischselbaum RR (eds), Cancer Medicine, Fifth Edition, pp. 1903-1930, Hamilton, ON.; B.C. Decker Inc. Publisher, 2000.

Brennan MF, Alektar K, Maki R. Soft tissue sarcoma. In DeVita VT Jr, Hellman S, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology (6th edition), pp. 1841-1890. Philadelphia, PA: J.B. Lippincott Co. , 2001

Screening

Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250:1233-1238.

Original description of the genetic basis of the Li-Fraumeni Syndrome

Bennicelli JL, Barr FG. Genetics and the biologic basis of sarcomas. Curr Opin Oncol 1999; 11:267.

Staging and Prognostic Factors

Coindre JM, Terrier P, Bui NB, et al: Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869-877.

Pisters PW, Leung DH, Woodruff JM, Shi W, Brennan MF. Analysis of prognostic factors in 1041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996;14:1679-1689.

These comprehensive prognostic factor studies outline clinicopathologic prognostic factors for local recurrence, distant metastasis, and sarcoma-specific survival. These reports confirm the clinical profile of the high-risk patient with extremity soft tissue sarcoma: the patient with a large (T2), high-grade, deep lesion.

Brennan MF. Staging of soft tissue sarcomas. Ann Surg Oncol 1999;6:8-9.

This editorial outlines a proposed modification of the staging system to stratify tumor size by less 5 cm, 5-9.9 cm, and >= 10 cm. This modification will likely be incorporated into the next version of the AJCC Staging System.

Biopsy Techniques

Arca MH, Biermann JS, Johnson TM, et al. Biopsy techniques for skin, soft-tissue, and bone neoplasms. Surg Oncol Clin North Am 1995;4:157.

Barth RJ, Merino MJ, Solomon D, et al: A prospective study of the value of core needle biopsy and fine needle aspiration in the diagnosis of soft tissue masses. Surgery 1992; 112:536-543.

Heslin MJ, Lewis JJ, Woodruff JM et al. Core needle biopsy for diagnosis of extremity soft tissue sarcoma. Ann Surg Oncol 1997;4:425.

Treatment of Localized Extremity Sarcoma

Rosenberg SA, Tepper JE, Glatstein EJ, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305-315.

This classic phase III trial established limb-sparing surgery as the standard approach to patients with localized sarcoma. Overall survival was comparable in the amputation and limb-sparing groups.

Lewis JJ, Leung D, Espat J, et al. Effect of reresection in extremity soft tissue sarcoma. Ann Surg 2000 231:655-663.

This very thought provoking paper from the MSKCC group suggests that patients that undergo 2 operations (excision followed by secondary re-excision) have improved survival as compared to patients treated with a single definitive operation. It is possible that these differences which are demonstrable by multivariate analysis may be related to referral or selection bias. It is unlikely that a randomized trial could ever be performed to evaluate this intriguing question. At the simplest level these data can be used to reassure patients that have undergone pre-referral R1 or R2 resection - they are not apparently at risk for worse outcome as compared to patients primarily referred to a multidisciplinary sarcoma unit.

Pre- and Postoperative Radiotherapy

Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197-203.

Pisters PWT, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859-868.

The above trials are the only phase III studies addressing the role of postoperative radiotherapy. Both trials demonstrated that adjuvant radiotherapy was associated with significant improvement in local-recurrence free survival without any significant change in overall survival.

Pollack A, Zagars GK, Goswitz MS, et al. Preoperative versus postoperative radiotherapy in the treatment of soft tissue sarcomas: A mater of presentation. Int J Radiat Oncol Biol Phys 1998; 42:63-572.

This retrospective non-randomized comparison of pre- versus postoperative radiotherapy suggested that local control may be improved for patients with measurable disease treated with preoperative radiation.

Treatment by Surgery Alone (Without Radiotherapy):

Baldini EH, Goldberg J, Jenner C, Manola JB, Demetri GD, Fletcher CD, Singer S. Long-term outcomes after function-sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin Oncol 1999;17:3252-3259.

Rydholm A, Gustafson P, Rooser B, et al. Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 1991; 9:1757-65.

These studies demonstrate that many patients with localized STS can be treated by surgery alone. However, precise clincopathologic criteria for selecting patients for unimodality therapy are currently lacking and further studies are necessary.

Adjuvant Chemotherapy

Tierney JF. Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 1997;350:1647-1654.

This high-quality meta-analysis has evaluated the aggregate individual data from 13 phase III trials. Significant improvement was noted for patients receiving adjuvant chemotherapy for local control, distant metastasis free survival, and disease free survival. There was no statistically significant difference in overall survival (p=0.08).

Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: Results of the Italian randomized cooperative trial. J Clin Oncol 19:1238-1247, 2001.

This represents the first published "second generation" adjuvant chemotherapy trial - with entry criteria restricted to high-risk patients (G3/4, T2) and using modern chemotherapy drugs and dosing (epirubicin and ifosfamide). The trial demonstrates improved disease-free and overall survival among patients randomized to receive adjuvant chemotherapy after local treatment (surgery +/- radiation). Nothwithstanding the positive findings in this trial, there remain considerable reservations about whether adjuvant chemotherapy should be considered the standard of care for patients with high-risk STS.

Bramwell VHC. Adjuvant chemotherapy for adult soft tissue sarcoma: Is there a standard of care? J Clin Oncol. 19:1235-1237, 2001.

This thoughtful editorial discusses the Italian study in detail and places these findings in the context of the existing literature. Perhaps the most compelling point brought forth in the editorial is that the management strategy for patients with soft tissue sarcoma needs to be individualized based on a host of clinicopathologic factors. As such treatment is best provided in the context of a multidisciplinary sarcoma unit where these complex issues can be focused for each patient.

Retroperitoneal Sarcomas

Heslin MJ, Lewis JJ, Nadler E, Newman E, Woodruff JM, Casper ES, Leung DH, Brennan MF. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 1997;15: 2832-2839.

Excellent prognostic factor analysis. Recurrence rates approximates 5%/year from the time of initial operation. Radiation therapy was the only significant factor for reduced risk of local recurrence. Complete surgical resection and histologic grade are the most significant prognostic factors for overall survival.

Lewis JJ, Leung DH, Woodruff JM, Brennan MF. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg 1998;228:355-365.

The best paper on retroperitoneal sarcomas in the literature.

Jaques DP, Coit DG, Hajdu SI, Brennan MF. Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Ann Surg 1990;212:51-59.

The only paper that reports the reasons for which patients are deemed unresectable at laparotomy.

Gastrointestinal Sarcomas

DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231:51-58, 2000.

Ng EH, Pollock RE, Munsell MF, Atkinson EN, Romsdahl MM. Prognostic factors influencing survival in gastrointestinal leiomyosarcomas. Implications for surgical management and staging. Ann Surg 1992;215:68-77.

These reports from MSKCC and MDACC demonstrate that complete surgical resection and histologic grade are the most important prognostic factors for patients with gastrointestinal sarcomas.

Metastatic Sarcoma

van Geel AN, Pastorino U, Jauch KW, Judson IR, van Coevorden F, Buesa JM, Nielsen OS, Boudinet A, Tursz T, Schmitz PI. Surgical treatment of lung metastases: the European Organization for Research and Treatment of Cancer - Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer 1996;77:675-682.

EORTC experience with thoracotomy and complete metastasectomy for metastatic STS. 54% 3-year survival among patients undergoing complete resection of metastatic disease.

Billingsley KG, Lewis JJ, Leung DH, Casper ES, Woodruff JM, Brennan MF. Multifactorial analysis of the survival of patients with distant metastasis arising from primary extremity sarcoma. Cancer 1999;85:389-395.

Excellent review of prognostic factors for patients with M1 disease. The median survival in a cohort of 230 patients was 11.6 months.

Billingsley KG, Burt ME, Jara E, Ginsberg RJ, Woodruff JM, Leung DH, Brannan MF. Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival. Ann Surg 1999;229:602-610; discussion 610-612.

Outcome for 719 patients with pulmonary metastases. Patients treated with complete resection had a median survival of 33 months and a 3-year actuarial survival of 46%. Long-term survival is possible in selected patients but is exceedingly rare - 9%.

Chemotherapy in Advanced Disease

Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 7:1276-1285, 1993.

Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 7:1269-1275, 1993.

Le Cesne A, Judson I, Crowther D, et al. Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol 14:2676-2684, 2000.

Patel SR. Dose-intensive chemotherapy for soft tissue sarcomas. ASCO Educational Booklet 453-457, 2000.

New Agents

Delaloge S, Yovine A, Taamma A, et al. Ecteinascidin-743: A marine-derived compound in advanced, pre-treated sarcoma patients - Preliminary evidence of activity. J Clin Oncol 19:1248-1255, 2001.

Taamma A, Riogrio M, Guzman C, et al. Phase I and Pharmacokinetic studies of Ecteinascidin-743, a new marine compound , administered as a 24-hour continuous infusion in patients with solid tumors. J Clin Oncol 19:1256-1265, 2001.

These 2 reports outline the activity of ET-743, an novel compound derived from the Caribbean marine tunicate Ecteinascidia tuminata. ET-743 has activity in advanced, highly pretreated STS. This agent and its role in STS will undoubtedly be the subject of intensive research over the next decade.

Selected Ongoing Clinical Trials

Intergroup Phase III Trial of ST1-571 in advanced GISTS. (S0033)

This study is a phase III randomized intergroup trial designed to evaluate the clinical activity of STI-571 in patients with unresectable or metastatic GIST expressing the kit receptor tyrosine kinase (CD-117). The trial randomizes patients to low dose STI-571 (400 mg daily) versus a high dose STI-571 (400 mg twice daily). The primary endpoint of the trial is survival. The accrual target is 600 patients in 24 months. As of June of 2001, the trial has accrued 300 patients.

RTOG-S-0120: A phase I/II study of preoperative radiotherapy with and without sugen-5416 in the management of low to intermediate grade soft tissue sarcoma of the extremity or trunk.

This phase I/II trial of the Radiation Therapy Oncology Group (RTOG) is designed to evaluate the radiosensitizing properties of the tyrosine kinase inhibitor/anti-angiogenesis compound SU-5416. This study is designed to evaluate the maximum tolerated dose of SU-5416 when combined with standard preoperative radiation (50 Gy in 25 fractions) for patients with primary or locally recurrent low or intermediate grade STS. The phase II component of the study designed to evaluate the quantitative anti-angiogenic effects of SU-5416 delivered at the MTD when combined with preoperative EBRT. A variety of correlative biologic studies are planned with this trial.

RTOG-S-0121: RTOG phase I/II study of preoperative chemotherapy, angiogenesis inhibitor SU-5416 and radiation therapy in the management of patients with high-grade STS of the extremities and trunk.

This phase I/II trial builds upon the toxicity profile of a sequential chemoradiotherapy regimen piloted in a recently completed RTOG sarcoma trial (95-14). The chemoradiotherapy regimen utilized consists of 3 cycles of MAID. The first two cycles of MAID are alternated with two 22 grade split courses of radiation (11 fractions each) for a total preoperative radiation dose of 44 Gy. This regimen is combined with dose escalation of the tyrosine kinase anti-angiogenesis inhibitor SU-5416 to establish the MTD of SU-5416 when combined with the chemoradiotherapy regimen employed in RTOG 95-14. The target accrual is 32-45 patients (depending on the number of patients required to complete the phase I portion of the trial).

RTOG S-0124: A phase II study of multimodality therapy for primary and recurrent retroperitoneal sarcomas

This phase II study is designed to evaluate the toxicity profile, response rates, and event-free outcome with a combined-modality treatment program for patients with localized resectable retroperitoneal sarcomas. Patients with intermediate or high-grade retroperitoneal sarcomas are treated with induction doxorubicin and ifosfamide-based systemic therapy (up to 4 cycles) followed by preoperative external-beam radiotherapy (45-50 Gy). This is in turn followed by surgical resection with intraoperative or postoperative radiation boost. The target accrual is 48 patients. The three RTOG studies outlined above seek to evaluate novel combined-modality treatment approaches for patients with localized extremity, trunk, and retroperitoneal sarcomas. As such, these studies represent very reasonable protocol-based options for the majority of patients with localized sarcoma seen by surgeons.

Recent Abstracts

Blanke CD, von Mehren M, Joensuu H, Roberts, PJ, Eisenberg B, Heinrich M, Druker B, Tuveson D, Dimitrijevic S, Silberman SL, Demetri GD. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, ST1571, in patients (Pts) with unresectable of metastatic gastrointestinal stromal tumors (GISTS) expressing C-KIT (CD-117). Proc Am Soc Clin Oncol 20:1, 2001.

Van Oosterom AT, Judson I, Verweij J, Di Paola E, van Glabbeke M, Dimitrijevic S, Nielsen O. STI 571, an active drug in metastatic gastrointestinal stromal tumors (GIST), and EORTC phase I study. Proc Am Soc Clin Oncol 20:2, 2001.

These two abstracts were presented at the 2001 ASCO Plenary Session. They represent the results of an EORTC Phase I and multicenter Phase II studies of STI-571. This agent is an orally available small molecule inhibitor of Abl, KIT and PDGFR. The EORTC Phase I study demonstrated that STI-571 is well tolerated with an MTD defined at 400 mg po twice daily. The dose limiting toxicities were grade IV febrile neutropenia and nausea/vomiting. The multicenter trial reported by Blanke and colleagues was a phase II randomized trial in which patients were randomized to a 400 or 600 mg daily oral dose of STI-571 for patients with unresectable or metastatic GIST expressing C-KIT. Grade III/IV toxicities were seen in 9 patients (26%). Partial response or stable disease was noted in 19 patients (54%) and 12 patients (34%), respectively. At the time of abstract presentation, no patient had progressed after achieving an objective response and the median survival of the patient population has not been reached. The overall STI-571 literature to date validate the concept of molecular targeted therapy for advanced solid tumors and provide the first evidence of effective systemic treatment for GISTs. These seminal abstracts will provide the first reports of a series of clinical investigative trials in GISTs and other solid tumors expressing C-KIT.

Demetri GD, Manola J, Harmon D, Maki RG, Seiden MV, Supko JG, Ryan DP, Puchlaski TA, Goss G, Merriam P, Waxman A, Slater S, Potter A, Quigley MT, Lopez T, Sancho MA, Guzman C, Jimeno J, Garcia-Carbonero R. Ecteinascidin-743 (ET-743) induces durable responses and promising 1-year survival rates in soft tissue sarcomas (STS): Final results of phase II and pharmacokinetic studies in the U.S.A. Proc Am Soc Clin Oncol 20:1406, 2001.

Le Cesne A, Blay J, Judson I, Van Oosterom A, Verweij J, Radford J, Lorigan P, Rodenhuis S, Di Paola ED, Van Glabbeke M, Jimeno J, Nielsen O. ET-743 is an active drug in adult soft-tissue sarcoma (STS): a STBSG-EORTC phase II trial. Proc Am Soc Clin Oncol 20:1407, 2001.

ET-743, a cytotoxic alkaloid derived from a marine organism, was evaluated in 3 parallel phase II studies in patients with gastrointestinal stromal tumors (GIST), pretreated patients with advanced STS, and untreated non-GIST STS (front line therapy). Preliminary evidence suggests that this agent may be active in non-GIST STS. Further studies with this drug are underway. Expect to hear more about ET-743 in STS in the near future.

Kraybill WG, Spiro I, Harris J, Ettinger D, Trotti A, Lucas D, Blum R, Eisenberg B. Radiation Therapy Oncology Group (RTOG) 95-14: a phase II study of neoadjuvant chemotherapy (CT) and radiation therapy (RT) in high risk (HR), high grade, soft tissue sarcomas (STS) of the extremities and body wall: a preliminary report. Proc Am Soc Clin Oncol 20:1389, 2001.

This phase II RTOG trial evaluated a preoperative combined-modality regimen consisting of 3 cycles of MAID; the first two of which were alternated with two 22 Gy courses of radiation (11 fractions each) for a total preoperative radiation dose of 44 Gy. This was followed by surgical resection with microscopic assessment of margins. An additional 16 Gy boost dose was delivered for microscopically positive surgical margins. Observed toxicities were significant with 27 (66%) patients and 12 (29%) patients experiencing grade IV neutropenia and thrombocytopenia, respectively. Notwithstanding these toxicities, 88% of patients completed preoperative chemotherapy and 93% completed preoperative radiotherapy. The 2-year actuarial survival was 95%. This preliminary report will require further follow-up. Nonetheless, the encouraging preliminary survival data support additional studies evaluating combined-modality therapy for patients with localized high-risk sarcoma.