Sarcoma

There is normally no role for regional lymphadenectomy in most adult patients with sarcoma because of the low (2% to 3%) prevalence of lymph node metastases. However, patients with angiosarcoma, embryonal rhabdomyosarcomas, synovial sarcoma, and epithelioid sarcomas have an increased incidence of lymph node involvement and should be examined and imaged for lymphadenopathy.

b. Adjuvant radiation therapy. Wide local excision alone is all that is necessary for small (T1), low-grade, soft-tissue sarcomas of the extremities, with local recurrence rate of less than 10%. Adjuvant RT, however, is required in a number of situations: (a) virtually all high-grade extremity sarcomas, (b) lesions larger than 5 cm (T2), and (c) positive or equivocal surgical margins in patients for whom re-excision is impractical. For T2 extremity soft-tissue sarcomas or any high-grade sarcomas, limb-sparing surgery plus adjuvant radiation to improve local control has become the standard approach. When adjuvant radiation is planned, metal clips should be placed at the margins of resection to facilitate radiation field.

c. Adjuvant chemotherapy. The benefit of adjuvant chemotherapy for most extremity soft-tissue sarcomas is controversial. A formal meta-analysis of individual data from 1,568 patients who participated in 13 trials was performed by the Sarcoma Meta-analysis Collaboration. The analysis demonstrated a significant reduction in the risk of local or distant recurrence in patients who received adjuvant chemotherapy. There was also a decrease in the risk of distant relapse (metastasis) by 30% in treated patients. Overall survival, however, did not meet the criteria for statistical significance between the control group and the adjuvant chemotherapy arm, with a hazard ratio of 0.89 (Lancet 1997;350:1647). Most of the randomized trials examined in this meta-analysis were limited by patient numbers, heterogeneous patient and disease characteristics, and varied chemotherapeutic regimens. However, a randomized trial of a homogeneous group of patients with high-grade soft-tissue sarcomas of the extremities and girdle demonstrated a significant survival advantage of five cycles of adjuvant ifosfamide (1.8 g/m² days 1 to 5) and epirubicin (60 mg/m² days 1 to 2) following definitive local therapy (J Clin Oncol 2001;19:1238). In this trial, the chemotherapy arm had an overall median survival of 75 months versus 46 months in the observation arm (p = 0.03). An additional trial demonstrated that three cycles of neoadjuvant ifosfamide and epirubicin was equivalent to five cycles of adjuvant therapy (J Clin Oncol 2012;30:850). The only exception is with rhabdomyosarcomas, in which neoadjuvant and adjuvant chemotherapy is accepted as standard of care.

d. Neoadjuvant radiotherapy. It may be necessary to administer radiation before definitive resection. This is most commonly performed for tumors that are borderline resectable or for tumors located adjacent to the joint capsule. The typical dose is 50 Gy. Sometimes, a boost is given postoperatively if margins are not adequate. Neoadjuvant radiation, however, is associated with wound healing difficulties. A phase III National Cancer Institute of Canada (NCIC) trial comparing adjuvant (postoperative) and neoadjuvant (preoperative) radiation demonstrated similar local control rates, metastatic outcome, and overall survival rates between the two arms (Lancet 2002;359:2235). However, patients receiving preoperative radiation had a significantly higher incidence of wound complications (35% vs. 17%).

e. Radiation as definitive therapy. RT alone in the treatment of unresectable or medically inoperable soft-tissue sarcoma patients yields a 5-year survival rate of 25% to 40% and a local control rate of 30%. Radiation doses, if feasible, should be at least 65 Gy.

f. Brachytherapy. Brachytherapy has also been used in treatment for sarcomas. Iridium 192 is the most commonly used agent. It has comparable local control rates versus adjuvant external-beam RT, although some data suggest a higher rate of wound complications and a delay in healing when the implants are after loaded before the third postoperative day. The advantages of brachytherapy include a decrease in the patient’s entire treatment to 10 to 12 days from 10 to 12 weeks, and the advantage that smaller volumes of tissue can be irradiated, which could improve functional results. However, smaller volumes may not be appropriate, depending on the tumor size and grade.

2. Retroperitoneal sarcomas

a. Surgery. As with other soft-tissue sarcomas, surgery is the primary treatment of retroperitoneal sarcomas. Tumors that are less than 5 cm in size and not located close to adjacent viscera or critical neurovascular structures are considered resectable. If a tumor has a high clinical suspicion of sarcoma and is resectable, it may not be necessary to perform a preoperative biopsy. One should consider a preoperative biopsy if an incomplete resection is a reasonable possibility to allow neoadjuvant therapy. If a biopsy is performed, it should be a CT-guided core biopsy.

Unfortunately, only 50% of patients with early stage retroperitoneal sarcomas are able to undergo complete surgical resection. Of the tumors removed, approximately half will develop a local recurrence. Adjuvant therapy, therefore, plays an important role in the management of retroperitoneal sarcomas.

b. Adjuvant and neoadjuvant RT. Adjuvant RT is most frequently recommended for patients with high-grade tumors or positive margins. The radiation is typically started 3 to 8 weeks following surgery to allow wound healing. Two-year local control rates of 70% have been reported with the addition of postoperative RT.

Neoadjuvant RT is used for patients with retroperitoneal sarcomas. It can be given to patients with marginally resectable tumors and those in whom one would expect to require postoperative radiotherapy. Neoadjuvant RT has a number of advantages over postoperative radiotherapy, including smaller radiation portals and reduction of the extent of the surgical procedure.

c. Management of unresectable locally advanced retroperitoneal sarcomas. Unresectable retroperitoneal sarcomas can be managed in a number of ways. RT can be given for palliation and with the hope that the tumor could be made resectable. Palliative surgery to reduce local symptoms can be performed. Chemotherapy can also be administered.

3. Visceral sarcomas

a. Overview. The discovery of the importance of a mutation in the tyrosine kinase c-KIT in GIST has led to a radical change in therapy for this sarcoma. Visceral leiomyosarcomas should be stained for c-KIT to rule out GIST.

b. Therapy for visceral sarcomas other than GIST

i. Surgery. Surgery is the primary treatment of visceral sarcomas.

ii. Adjuvant and neoadjuvant radiation. Adjuvant RT is necessary if the tumor is high grade or if margins are positive. It is usually started 3 to 8 weeks following surgery to allow wound healing. Neoadjuvant radiation can be considered to allow a less radical surgery or make a previously unresectable tumor operable.

iii. Management of unresectable locally advanced visceral sarcomas. Unresectable intra-abdominal sarcomas can be managed in a number of ways. RT can be given for palliation and with the hope that the tumor could be made resectable. Palliative surgery to reduce local symptoms can be performed. Chemotherapy can also be administered.

c. Therapy for GIST. Like other sarcomas, surgery is the primary therapy for nonmetastatic GIST tumors. Imatinib is a small-molecule tyrosine kinase inhibitor with significant inhibitory activity against c-KIT. In the initial study, 147 patients with metastatic GIST were treated with either imatinib 400 mg/m² or 600 mg/m² daily. Partial responses were noted in 54% and stable disease in 28% (N Engl J Med 2002;347:472). The initial dose of imatinib is 400 mg daily, which should be continued until the disease progresses. Upon disease progression, treatment options include higher doses of imatinib (600 or 800 mg/day) or the use of sunitinib, another tyrosine kinase inhibitor, which has shown activity in imatinib-resistant GIST. An option for third-line therapy is regorafenib (Lancet 2013;381:295).

If a tumor is marginally resectable or the surgery would result in significant morbidity, neoadjuvant therapy with imatinib can be given for 3 to 6 months. Of note, it may take 4 months or more to observe a response to imatinib on CT scan, although changes in FDG-PET imaging can be seen very rapidly (within days).

B. Treatment of local recurrence. Local recurrence of soft-tissue sarcomas should be treated with surgical resection whenever feasible. Adjuvant radiation is often used. For unresectable recurrence of disease, radiation is preferred.

C. Treatment of metastatic soft-tissue sarcomas

1. Overview. Metastatic soft-tissue sarcomas can be divided into limited metastasis and extensive metastasis. Limited metastatic disease is defined as resectable metastasis involving one organ system. The prognosis of these two subsets of patients is very different. It is possible (though unlikely) to cure limited metastatic disease, whereas patients with extensive metastatic disease can only be palliated.

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