• Soft Tissue Cancers
• Radiology
• Adjuvant/Neoadjuvant Therapy

• Oncology
• Soft Tissue Cancers
• Radiology
• Adjuvant/Neoadjuvant Therapy

An improved understanding of tumor biology and relevant surgical anatomy has led to advances in therapy for bone and soft tissue sarcoma over the past 50 years. Substantial progress has been made in surgery, radiation therapy, and systemic therapy, offering patients with sarcoma hope for successful treatment and a meaningful quality of life.

Robert M. Henshaw, MD, Georgetown University, Washington, D.C., USA opened with a discussion of surgical advances in bone and soft tissue sarcoma. Fifty years ago, more than 80% of patients with osteosarcoma were dead within 2 years after immediate radical amputation. Advances in surgical management concurrent with advances in knowledge of pathology, diagnostic techniques (ie, closed needle biopsy), musculoskeletal imaging, and local and systemic adjuvant treatments have resulted in much better outcomes. A prognostically significant, standardized staging system for sarcomas, based on low grade versus high grade and intracompartmental versus extracompartmental parameters (introduced by William Enneking), is still in use today [Enneking WF et al. Clin Orthop Relat Res 1980].

Multiaxial imaging allows for better planning of limb-sparing oncologic resection, as surgeons can distinguish abnormal from normal tissue in areas of anatomic complexity (ie, shoulder girdle and pelvis) [Aboulafia AJ et al. Cancer 1993; Malawer MM et al. Surgery 1985]. Limb-sparing surgery has gained wide acceptance with improved methods of endoprosthetic reconstruction following surgical resection, said Dr. Henshaw, including the use of modular implants that allow for the early return to function [Zeegen EN et al. Clin Orthop Relat Res 2004; Henshaw RM et al. Current Opinion Ortho 2003]. Preparatory solutions, antibiotic coverage, and the use of antiseptic soaps before wound closure have all helped to reduce the risk of infection with endoprosthetic reconstruction, which is the most common reason for implant failure.

With the acceptance of limb-sparing surgery, attention has turned to improving functional outcomes and quality of life measures associated with the procedure. Enneking et al. [Clin Orthop Relat Res 1993] published a simplified functional outcome scoring system in 1993 that was adopted by the Musculoskeletal Tumor Society. Most patients with sarcomas are now candidates for limb-sparing surgery, with functional outcomes superior to those with amputation.

Percutaneous thermal ablation of sarcomas, especially in patients with metastatic disease or local recurrence, is promising.

Dian Wang, MD, PhD, Rush University, Chicago, Illinois, USA, noted that radiotherapy technologies for soft tissue sarcoma have evolved to enhance the planning and delivery of radiotherapy, with significant reductions in toxicity. The goal of radiotherapy in this setting is to give a higher dose to the tumor and a lower dose to critical normal organs and tissues. Specifically, he pointed to image-guided radiotherapy (IGRT) and image-guided intensity-modulated radiation therapy (IG-IMRT).

IGRT permits precise tumor localization on a periodic basis to ensure coverage of target volumes, including gross tumor volume and clinical target volume. With IGRT, pretreatment images are acquired on a treatment day to evaluate tumor location relative to its location on the day of computed tomography simulation and radiation planning.

IGRT may be most beneficial for patients treated with IMRT, which renders highly conformal dose distributions with steep dose gradients (fall off dose). Precise localization is key when using IMRT, as the high dose of radiation delivered increases the risk to critical adjacent normal organs. The smaller margins enabled by IG-IMRT lessen the toxicity borne by normal tissues and allow for optimization of the radiation dose to the target tissue.

Function-preserving surgery with adjuvant RT has replaced amputation as the primary local treatment of choice for soft tissue sarcoma. In 1998, limb-sparing surgery plus radiation was shown to improve local control over limb-sparing surgery in patients with both high-grade and low-grade extremity soft tissue sarcoma (chemotherapy was given to treat high-grade soft tissue sarcoma in both arms of that Phase 3 trial) [Yang JC et al. J Clin Oncol 1998]. In general, adjuvant RT is associated with a local control of approximately 90% for margin-negative soft tissue sarcoma and 80% for margin-positive disease.

Preoperative RT is equivalent to postoperative RT in local control and is associated with less chronic toxicities such as grade 2+ fibrosis, joint stiffness, and edema, but with an increase in the rate of acute wound complications, mainly in lower extremity soft tissue sarcoma [O'Sullivan et al., Lancet 2002; Davis AM et al. Radiother Oncol 2005]. The results of RTOG 0630 showed that preoperative IG-IMRT could significantly reduce late morbidity due to a smaller RT field volume and a reduced RT dose. This observation was also documented through a single institutional Phase 2 trial [O'Sullivan B et al. Cancer 2013]. Preoperative IG-IMRT might also facilitate resection and reduce the risk of tumor seeding during surgery, said Dr. Wang.

Shreyaskumar R. Patel, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, USA, provided an overview of advances made in systemic therapy. He noted that the therapeutic potential of chemotherapy was maximized once dose intensification became feasible in the 1990s as a result of better supportive care and the availability of growth factors.

For bone tumors, the routine use of primary chemotherapy such as doxorubicin, cisplatin, high-dose methotrexate and ifosfamide has improved the cure rate of high-grade extremity osteosarcomas to around 60% to 70% [Mirabello L et al. Cancer 2009]. The most important predictive factor for long-term outcome for patients with osteosarcoma receiving preoperative chemotherapy is the percent tumor necrosis, which can help tailor therapy. Emerging data suggest that functional imaging can help identify the poor responders to conventional chemotherapy [Costelloe CM et al. J Nuc Med 2009]. The addition of muramyl tripeptide phosphatidyl ethanolamine to chemotherapy has improved event-free survival in osteosarcoma; although approved in Europe, its use is still under investigation in the USA [Meyers PA et al. J Clin Oncol 2008].

For localized Ewing sarcoma, the routine use of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide improves cure rates to around 50% to 60% [Granowetter L et al. J Clin Oncol 2009]. Unfortunately, response rates and survival have plateaued, with little progress made over the past 2 decades. Targeted agents, such as humanized monoclonal antibodies against the insulin-like growth factor-1 and mammalian target of rapamycin inhibitors, have had a limited durability of response and there are no relevant biomarkers with which to identify likely responders.

Soft tissue sarcomas have lower sensitivity to available agents than do osteosarcomas or Ewing sarcoma, and thus the treatment success has been less impressive. The numerous subtypes of adult soft tissue sarcoma have made clinical trials of appropriate dose-intensive regimens in individual histologies difficult to conduct, said Dr. Patel. First-line systemic therapy remains doxorubicin with/without ifosfamide, whereas gemcitabine and docetaxel are considered second-line. The vascular endothelial growth factor receptor inhibitor pazopanib improves progression-free survival from 1.6 months to 4.6 months when compared with placebo [van der Graaf WT et al. Lancet 2012].

Early evidence for the activity with targeted therapy (ie, imatinib) in subsets of patients, such as those with gastrointestinal stromal tumors [Joensuu H et al. JAMA 2012], is encouraging but targeted therapies tested in the more common bone and tissue sarcomas have only had modest success. The lack of oncogenic drivers and actionable targets for bone and soft tissue sarcomas with complex genomic profiles has been the major limitation encountered.

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