Kevin A. Raskin

Treatment and Outcome of 82 Patients with Angiosarcoma

BackgroundAngiosarcomas are an uncommon type of malignancy that are generally thought to behave usually in a locally aggressive fashion; they often metastasize to distant sites.MethodsPatients with a diagnosis of angiosarcoma treated at our institution between 1980 and 2006 were analyzed for patient demographics, tumor characteristics, multimodality treatment, and outcomes.ResultsA total of 82 patients were divided into those with primary and advanced disease. Overall, the median age was 65 (range, 22–91) years, and 44% of patients were women. Median size of tumors was 3.8 cm, and 76% of tumors were intermediate or high grade. Tumors were located throughout the body: 32 cutaneous, 22 deep soft tissues or organs, 10 radiation or lymphedema field, 8 bone, and 7 nonirradiated breast. Of 46 patients with primary disease, all patients underwent surgical resection, 67% received radiotherapy, and 27% received chemotherapy. Five-year disease-specific survival was 60%, and negative prognostic factors included intermediate or high grade, and tumors arising in a radiated or lymphedema field. Of 36 patients with advanced disease, 36% underwent a palliative operation, 78% received radiation, and 58% received chemotherapy. Median survival was just 7.3 months, and cutaneous tumors predicted a better prognosis compared with other sites.ConclusionsPrimary angiosarcomas treated with aggressive surgical resection and the addition of radiation for close margins or worrisome pathologic features can result in long-term survival in most patients. The role of adjuvant chemotherapy is unclear. Patients with advanced disease have a poor prognosis, but there can be dramatic responses to chemotherapy in a minority of patients.

Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas

PURPOSE Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of >or=66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. METHODS AND MATERIALS Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewings sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. RESULTS A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. CONCLUSIONS Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

Infection in massive bone allografts.

We studied a series of 945 patients who received cadaveric allografts implanted for nonpelvic bone or soft tissue tumor lesions since 1971. We specifically were interested in the role of infection in the graft process, and, more specifically its history, frequency, and affect on outcome. Primary infections (not related to reoperations for nonunions or fractures of the graft) occurred in 75 patients (7.9%), and an additional 46 patients had infections related to reoperations, increasing the total number of patients with infections to 121 (12.8%). The highest frequency of infection occurred in patients with soft tissue tumors, radiated sites, Musculoskeletal Tumor Society Stage IIB tumors, or surgeries consisting of an allograft arthrodesis. Most of the infected grafts failed; however, none of the patients died. One patient had hepatitis C develop, and one patient became HIV positive after receiving the virus from a blood transfusion. A comparison with other series of surgically treated patients, including those receiving metallic devices, suggests that the infection rate may be related to the surgery or the graft’s immunologic resistance, rather than the graft. The problem of infection is a major issue for tumor surgeons. Suggestions regarding how to decrease the frequency of this complication are presented. Level of Evidence: Therapeutic study, Level IV (case series-no, or historical control group). See the Guidelines for Authors for a complete description of levels of evidence.

Survival data for patients with malignant schwannoma.

Malignant schwannomas are uncommon sarcomas that arise from the sheath of Schwann surrounding peripheral nerve fibers. These tumors may arise spontaneously in adult patients or may occur with reportedly increased frequency in patients with neurofibromatosis Type I. The tumors have had a reputation for malignancy with rapid metastasis, especially when they arise in relation to neurofibromatosis. We have reviewed the experience of the connective tissue oncology unit with patients with these tumors during the past 25 years. There were 80 malignant schwannomas identified in 41 females and 39 males with a mean age of 36 ± 17 years. The largest numbers of tumors were seen in the thigh, shoulder, and pelvis but they also occurred in more central (abdomen and thorax) and distal (forearm, hand and foot) locations. The Musculoskeletal Tumor Society stages showed that the majority of the patients had Stage II (high grade but not metastasized) tumors; however, additionally, 10 of the patients had metastases at outset (Stage III). Patient gender was not a factor but stage was a notable determinant of survival. Anatomic location also had a significant effect. Overall, the entire series of patients had a survival of 85% at 11 ± 5 years and even more remarkable was the fact that there was no difference between the numbers and outcome statistics for tumors arising spontaneously and those occurring in patients with neurofibromatosis.

Giant Cell Tumor of Bone

&NA; Giant cell tumor (GCT) of bone is one type of giant cell‐rich lesion of bone. This benign mesenchymal tumor has characteristic multinuclear giant cells. Mononuclear stromal cells are the physiologically active and diagnostic cell type. Most GCTs are located in the epiphyseal regions of long bones. The axial skeleton—primarily the sacrum—is a secondary site of involvement. Most patients present with pain, swelling, joint effusion, and disability in the third and fourth decades of life. Imaging studies are important for tumor staging and radiographic grading. Typically, these clinically active but slow‐growing tumors are confined to bone, with relatively well‐defined radiographic borders. Monostotic disease is most common. Metastatic spread to the lungs is rare. Extended intralesional curettage with or without adjuvant therapy is the primary treatment choice. Local recurrence is seen in ≤20% of cases, and a second local intralesional procedure is typically sufficient in cases that are detected early. Medical therapies include diphosphonates and denosumab. Denosumab has been approved for use in osteoporosis as well as breast and prostate cancer metastatic to bone. Medical therapy and radiotherapy can alter the management of GCT of bone, especially in multifocal disease, local recurrences, and bulky central/axial disease.

Proton-Based Radiotherapy for Unresectable or Incompletely Resected Osteosarcoma

A study was undertaken to assess clinical outcome and the role of proton therapy for local control of osteosarcoma (OSA).

Proton radiotherapy for pediatric Ewing's sarcoma: initial clinical outcomes.

PURPOSE Proton radiotherapy (PT) has been prescribed similarly to photon radiotherapy to achieve comparable disease control rates at comparable doses. The chief advantage of protons in this setting is to reduce acute and late toxicities by decreasing the amount of normal tissue irradiated. We report the preliminary clinical outcomes including late effects on our pediatric Ewings sarcoma patients treated with PT at the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital (Boston, MA). METHODS AND MATERIALS This was a retrospective review of the medical records of 30 children with Ewings sarcoma who were treated with PT between April 2003 and April 2009. RESULTS A total of 14 male and 16 female patients with tumors in several anatomic sites were treated with PT at a median age of 10 years. The median dose was 54 Gy (relative biological effectiveness) with a median follow-up of 38.4 months. The 3-year actuarial rates of event-free survival, local control, and overall survival were 60%, 86%, and 89%, respectively. PT was acutely well tolerated, with mostly mild-to-moderate skin reactions. At the time of writing, the only serious late effects have been four hematologic malignancies, which are known risks of topoisomerase and anthracyline exposure. CONCLUSIONS Proton radiotherapy was well tolerated, with few adverse events. Longer follow-up is needed to more fully assess tumor control and late effects, but the preliminary results are encouraging.

β-Catenin Mutation Status and Outcomes in Sporadic Desmoid Tumors

BACKGROUND Mutations in the gene-encoding β-catenin, CTNNB1, are highly prevalent in sporadic desmoid tumors and may predict the risk for recurrence. We sought to determine the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoid tumors and to determine whether CTNNB1 mutation status correlates with disease outcome. METHODS Single-base extension genotyping of the CTNNB1 gene was performed on 145 sporadic, paraffin-embedded desmoid tumor specimens. Correlation of mutation status with outcome was performed on a subset of 115 patients who underwent macroscopically complete surgical resection. RESULTS CTNNB1 mutations were detected in 106 of 145 (73%) tumor specimens and in 86 of 115 (75%) specimens from patients who underwent curative-intent surgical resection, including discrete mutations in the following codons of CTNNB1 exon 3: T41A (46%), S45F (25%), S45P (1.7%), and S45C (0.9%). Desmoid tumors of the superficial trunk were significantly less likely to harbor CTNNB1 mutations than tumors located elsewhere, but none of the other examined clinicopathologic factors were found to be associated with CTNNB1 mutation status. At a median follow-up of 31 months, 5-year recurrence-free survival was slightly, although not statistically significantly, worse for patients with β-catenin-mutated tumors than for those with wild-type tumors (58% vs. 74%, respectively). The specific CTNNB1 codon mutation did not correlate with the risk for recurrence. CONCLUSION CTNNB1 mutations are indeed common in sporadic desmoid tumors. However, our study did not detect a statistically significant difference in recurrence risk according to either the CTNNB1 mutation status or the specific CTNNB1 mutation.

COMBINATION SHORT-COURSE PREOPERATIVE IRRADIATION, SURGICAL RESECTION, AND REDUCED-FIELD HIGH-DOSE POSTOPERATIVE IRRADIATION IN THE TREATMENT OF TUMORS INVOLVING THE BONE

PURPOSE To assess the feasibility and outcomes of combination short-course preoperative radiation, resection, and reduced-field (tumor bed without operative field coverage) high-dose postoperative radiation for patients with solid tumors mainly involving the spine and pelvis. METHODS AND MATERIALS Between 1982 and 2006, a total of 48 patients were treated using this treatment strategy for solid tumors involving bone. Radiation treatments used both photons and protons. RESULTS Of those treated, 52% had chordoma, 31% had chondrosarcoma, 8% had osteosarcoma, and 4% had Ewings sarcoma, with 71% involving the pelvis/sacrum and 21% elsewhere in the spine. Median preoperative dose was 20 Gy, with a median of 50.4 Gy postoperatively. With 31.8-month median follow-up, the 5-year overall survival (OS) rate is 65%; 5-year disease-free survival (DFS) rate, 53.8%; and 5-year local control (LC) rate, 72%. There were no significant differences in OS, DFS, and LC according to histologic characteristics. Between primary and recurrent disease, there was no significant difference in OS rates (74.4% vs. 51.4%, respectively; p = 0.128), in contrast to DFS (71.5% vs. 18.3%; p = 0.0014) and LC rates (88.9% vs. 30.9%; p = 0.0011) favoring primary disease. After resection, 10 patients experienced delayed wound healing that did not significantly impact on OS, DFS, or LC. CONCLUSION This approach is promising for patients with bone sarcomas in which resection will likely yield close/positive margins. It appears to inhibit tumor seeding with an acceptable rate of wound-healing complications. Dose escalation is accomplished without high-dose preoperative radiation (likely associated with higher rates of acute wound healing delays) or large-field postoperative radiation only (likely associated with late normal tissue toxicity). The LC and DFS rates are substantially better for patients with primary than recurrent sarcomas.

An Effective Preoperative Three-Dimensional Radiotherapy Target Volume for Extremity Soft Tissue Sarcoma and the Effect of Margin Width on Local Control

PURPOSE There is little information on the appropriate three-dimensional (3D) preoperative radiotherapy (XRT) volume for extremity soft-tissue sarcomas (STS). We retrospectively analyzed the pattern of local failure (LF) to help elucidate optimal field design. METHODS AND MATERIALS We analyzed the 56 patients who underwent computed tomography-planned XRT for Stage I to III extremity STS between June 2000 and December 2006. Clinical target volume (CTV) included the T1 post-gadolinium-defined gross tumor volume with 1- to 1.5-cm radial and 3.5-cm longitudinal margins. Planning target volume expansion was 5 to 7 mm, and >or=95% of dose was delivered to the planning target volume. Preoperative XRT was 44 to 50.4 Gy (median, 50). Postoperative boost of 10 to 20 Gy was given to 12 patients (6 with positive and 6 with close margins). RESULTS Follow-up ranged from 15 to 76 months (median, 41 months). The 5-year local control, freedom from distant metastasis, disease-free survival, and overall survival were 88.5%, 80.0%, 77.5% and 82.8%, respectively. Three patients (all with positive margin) experienced local failure (LF) as first relapse (2 isolated, 1 with distant failure), and 2 additional patients (all with margin<1 mm) had late LF after distant metastasis. The LFs were within the CTV in 3 patients and within and also extending beyond the CTV in 2 patients. CONCLUSIONS These target volume definitions appear to be appropriate for most patients. No local recurrences were observed with surgical margins >or=1 mm, and it appears that these may be adequate for patients with extremity STS treated with preoperative radiotherapy.