Experts discussed their approach to the diagnosis and management of three very different types of soft tissue sarcoma (STS)—myxoid liposarcoma, peripheral nerve sheath tumors, and alveolar soft part sarcoma—during the Clinical Problems in Oncology Session “How I Treat Specific Sarcoma Histologic Subtypes” held June 3. The session highlighted the challenges of treating rare cancers and the power of collaboration.
In contrast to more common cancers, in which large clinical trials are often available to generate evidence-based medicine, some of these sarcoma subsets are fairly rare and standard treatments have not been established. However, for each sarcoma type discussed, strategies are being developed—whether surgical, medical, or radiologic—with the aim of improving outcomes for patients with sarcoma.
Dr. Scott H. Okuno speaks during the Education Session “How I Treat Specific Sarcoma Histologic Subtypes.”
Update on Myxoid Liposarcoma
Session Chair Scott H. Okuno, MD, of the Mayo Clinic, reviewed the clinical presentation, diagnosis, and treatment of myxoid liposarcoma, highlighting its differences from other STSs.
Myxoid liposarcoma accounts for about one-third of liposarcomas. It affects men and women equally, and, with diagnoses peaking at about age 40 to 50, patients are generally younger than those with other types of liposarcoma. In terms of disease site, about two-thirds of cases develop in the thigh.
Diagnosis is achieved by biopsy and confirmed based on the presence of a reciprocal translocation between chromosomes 12 and 16 resulting in a DDITS-FUS gene fusion. Translocations between chromosomes 12 and 22 are observed in rare cases.
Staging studies should include a CT scan of the chest, abdomen, and pelvis. Dr. Okuno explained that, in contrast to other sarcomas that often metastasize to the lung, myxoid liposarcoma has a predilection to metastasize to the bone, particularly the spine. However, multiple imaging modalities, including bone scans, PET scans, and CT scans, cannot detect these masses. MRI can be useful for detecting spinal metastases and is therefore an important imaging tool for myxoid liposarcoma.
Dr. Okuno emphasized that if someone has pain and their regular imaging, PET scan, and bone scan do not show disease, “Don’t stop,” he said. “You have to go further and probably do an MRI.”
Determining the round cell component is an important part of the assessment, as higher percentages of round cells are associated with an increased risk of recurrence and metastasis and a poorer prognosis. Although tumor size is also predictive of recurrence, Dr. Okuno considers the round cell component to be a more important indicator.
Other factors associated with poor prognosis include high histologic grade, necrosis, and p53 overexpression. Older age and tumor size larger than 10 cm have also been associated with a higher risk of recurrence. Additional molecular factors are being studied as potential prognostic markers.
The standard treatment approach for myxoid liposarcoma is surgical resection. Adjuvant chemotherapy may be used for patients with high-grade tumors and those with at least 5% round cells. The doxorubicin plus epirubicin and ifosfamide combination is used in the adjuvant and first-line metastatic settings.
Several new therapies have been introduced in recent years, providing needed treatment options for patients with myxoid liposarcoma. Trabectedin is approved by the U.S. Food and Drug Administration for patients with liposarcoma and leiomyosarcoma who have already received anthracycline-based chemotherapy. The approval was based on the progression-free survival benefit of trabectedin compared with dacarbazine in liposarcoma cases, of which 11% were myxoid liposarcomas.
Retrospective data in a selected myxoid liposarcoma population have shown good activity with trabectedin among previously treated patients with a higher round cell component. However, in a phase III trial of patients with a variety of translocation-associated sarcomas, there was no difference in efficacy between trabectedin and doxorubicin-based therapy.
Eribulin has also demonstrated activity among patients with metastatic STS and could be considered for patients who require treatment and have already received trabectedin. In a randomized, open-label, phase III trial, eribulin was associated with a significant survival benefit over dacarbazine in a population of patients with advanced STS, of whom 13% had myxoid liposarcoma (overall survival, 13.5 vs. 11.5 months, respectively; hazard ratio [HR] 0.77, 95% CI [0.62, 0.95]; p = 0.0169).
Looking ahead, several investigational treatment strategies are being evaluated in clinical trials, including the novel activator of PPAR-γ efatutazone and various immunotherapeutic strategies, including adaptive T-cell approaches. “There are some strategies that I think are going to evolve over time to help these patients with myxoid liposarcoma,” Dr. Okuno concluded.
New Approaches for Peripheral Nerve Sheath Tumors
Brigitte C. Widemann, MD, of the National Cancer Institute, reviewed the diagnosis, natural history, and management of malignant peripheral nerve sheath tumors (MPNSTs). She focused on prevention of MPNSTs, given that the treatment options, other than surgery, are limited.
MPNSTs are aggressive malignancies that account for only 4% of STSs. About half are associated with the genetic condition neurofibromatosis type 1 (NF1) and develop in pre-existing plexiform neurofibroma. The remainder occur spontaneously. Dr. Widemann noted that the clinical signs and symptoms of MPNSTs overlap with those of plexiform neurofibroma. The management of MPNSTs is difficult, as the only curative approach is complete surgical resection with wide negative margins. No effective medical therapies have been established, and outcomes for these patients have not improved over time. However, Dr. Widemann said that a growing understanding of the natural history of MPNSTs and genetic factors associated with their development have resulted in some renewed hope.
MPNSTs account for only one type of peripheral nerve sheath tumor that can develop in patients with NF1. A variety of tumor types have been identified that differ in appearance, symptoms, age of onset, and pathologic findings. These include cutaneous neurofibroma, plexiform neurofibroma, and the more recently identified atypical neurofibroma, which does not tend to develop in children but rather in slightly older individuals. There has been great interest in the characterization of atypical neurofibroma as it is now understood to be a precursor to MPNST, along with plexiform neurofibroma.
Dr. Widemann and her colleagues have been using volumetric MRI to analyze the natural history of both plexiform neurofibroma and atypical neurofibroma. In some patients, the researchers identified distinct nodular lesions that exhibit a more rapid growth rate. Although plexiform neurofibroma typically grows most rapidly in young patients, these nodular lesions grow independent of age, suggesting a different biology.
Dr. Widemann and colleagues recently published results of a phase I study showing that the MEK inhibitor selumetinib induces partial responses among children with NF1 and plexiform neurofibroma, as well as improvements in appearance and clinical symptoms. “However, we don’t know at this point if MEK inhibition will be important for these distinct nodular lesions,” she said.
Dr. Widemann noted that detecting malignant transformation in patients with NF1 remains challenging and better biomarkers are needed. Stable tumor volume and apparent reduction in FDG-PET uptake can be falsely reassuring, she warned, and “even regular evaluation may not allow for timely detection of malignant transformation.” Dr. Widemann said that new pain should raise concern in these patients.
For patients with atypical neurofibromas, data suggest that surgical resection may prevent the development of MPNSTs and resection may be effective for controlling disease even if microscopic margins are present, Dr. Widemann said.
Alveolar Soft Part Sarcoma
Dr. Silvia Stacchiotti speaks during the Education Session “How I Treat Specific Sarcoma Histologic Subtypes.”
ASPS arises through a translocation between the chromosomes X and 17 that results in the ASPLCR1-TFE3 fusion gene, causing the activation of MET. Platelet-derived growth factor receptor and vascular endothelial growth factor receptor are also overexpressed, suggesting a rationale for antiangiogenic therapy for patients with ASPS.
Dr. Stacchiotti explained that ASPS does not respond to the cytotoxic chemotherapy regimens used for other STSs. Although MET inhibitors, antiangiogenic agents, and immunotherapy are all being evaluated in ASPS, no treatments are approved for the first-line treatment of ASPS. The standard initial treatment of localized STS is surgery. Dr. Stacchiotti noted that wide excision of the tumor is important given the high rate of metastasis observed in published series. He said that radiation therapy may also be appropriate after surgery for select patients.
A variety of targeted therapies have been evaluated in ASPS. A small series showed that sunitinib can induce long-lasting responses. The CASPS study (Abstract 11004), presented at this year’s Annual Meeting, demonstrated activity with the antiangiogenic agent cediranib, with a reported response rate of 21%. Pazopanib demonstrated similar activity.
MET inhibitors are also being evaluated in patients with ASPS. Tivantinib induced no responses, but resulted in stable disease. Results are awaited from the phase II EORTC CREATE trial evaluating crizotinib in various tumors associated with ALK and/or MET activation. Preliminary data presented at this year’s Annual Meeting also suggest that checkpoint inhibition may have activity in patients with ASPS, although only small numbers of patients have been evaluated thus far.
–Melinda Tanzola, PhD