Because of the unpredictable natural history of DT and surgical challenges, there has been recent interest in nonsurgical strategies that are guided by certain patient and clinical factors.
Desmoid tumors (DTs), also known as aggressive fibromatosis, are locally aggressive, nonmetastatic neoplasms that are difficult to manage and require multidisciplinary care. Approximately 5 to 10 percent of DTs arise in the setting of familial adenomatous polyposis, with the remainder occurring via sporadic mutations in the CTNNB1 gene encoding ß-catenin. DTs most commonly occur in the abdominal wall and mesentery, but can arise in the extremities and head and neck region as well. Biopsy is critical for diagnosis before initiating treatment to differentiate DT from other soft-tissue tumors.
Historically, treatment of DTs consisted of wide surgical resection, which can be associated with significant functional morbidity because of the tumor location and/or size. Unfortunately, given the aggressive and infiltrative growth patterns, local recurrence remains a significant issue, with up to 30 percent of patients experiencing a recurrence even after a margin-negative resection.1 Because of the unpredictable natural history of DTs and surgical challenges, there has been recent interest in nonsurgical strategies that are guided by certain patient and clinical factors (see Table 1). Additional treatment options include active surveillance, radiation therapy (RT), cryoablation, and novel medical therapies.
Table 1. Patient or tumor factors that influence timing and type of treatment
Although previously considered a primarily surgical disease, current guidelines advocate for active surveillance in patients with asymptomatic, locally resectable DTs; intervention is reserved for tumors that are either symptomatic, impair or threaten function, or may limit local therapy options if they progress further (see Figure 1).2 These recommendations have evolved based on several recent retrospective studies demonstrating progression-free survival rates of 50 percent at five years for asymptomatic patients managed with active surveillance,3-5 similar to patients treated with primary medical therapies. However, this strategy requires reliable patient follow-up and re-evaluation of multidisciplinary treatment plans if there is significant tumor growth or development of symptoms.
Figure 1. Guidelines for patients with asymptomatic, locally resectable DTs
RT is an alternative standard local therapy for extra-mesenteric DTs. Tumor location and tumor size are a less-limiting factor for RT than they may be for surgical resection given modern conformal RT techniques that allow for maximized tumor control and minimized toxicities. For patients with DTs, RT is commonly employed in the definitive setting, and some encourage postoperative RT following an R1/R2 resection. Regardless of whether RT is delivered definitively or postoperatively, conventionally fractionated RT over the course of five to six weeks provides favorable local control outcomes, upward of 70 to 80 percent in most patients.6-8 However, the oncology community increasingly recognizes that tumor control is not uniformly favorable across all patient groups, and, therefore, patient selection is essential. Given the durable local control in most patients who receive RT, it remains an integral component in the management of DTs, either as an upfront or a salvage therapy.
As nonsurgical therapies are increasingly pursued, percutaneous cryoablation has been explored as primary and salvage treatment.9-11 Cryoablation involves computed tomography-guided insertion of cryoprobes with the goal to treat tissue 5mm beyond the tumor margin. Multiple and repeat ablations are possible for recurrence or incomplete ablation. Data are relatively limited but early results are encouraging, with reported high rates of stable disease and symptomatic improvement.9,11 This strategy is promising, but continued research is required before it becomes a standard upfront therapy; ongoing clinical trials (NCT02476305) are actively enrolling patients.
These studies and the increased availability of alternative systemic agents have necessitated reconsideration of the role of older treatments.
Several studies in recent years have shed light on the natural history of DT and demonstrated the efficacy of newer agents in this disease. A randomized, placebo-controlled phase III study of the tyrosine kinase inhibitor (TKI) sorafenib was notable, not only for RECIST (Response Evaluation Criteria in Solid Tumors) responses in 33 percent of patients receiving active therapy, but also 20 percent of patients receiving a placebo.12 This demonstrated not only the activity of the drug, but also documented prospectively for the first time the phenomenon of spontaneous regression of DTs in a subset of patients receiving placebo and supported an initial trial of active surveillance for asymptomatic DTs. Another recent study compared the TKI pazopanib against methotrexate and vinblastine—an older standard chemotherapy regimen—and showed that pazopanib had a higher rate of nonprogression at six months (86 percent versus 50 percent) with improved pain control in the TKI arm.13
These studies and the increased availability of alternative systemic agents have necessitated reconsideration of the role of older treatments. Therapies like tamoxifen, imatinib, and NSAIDs all have modest response rates in single-arm studies, which are not clearly superior to the placebo arm of the sorafenib study. Moreover, while doxorubicin-based therapies have high response rates,14,15 the acute and potential long-term toxicity of these treatments should limit their use to cases where a response urgently is needed.
Finally, a randomized phase III study with the gamma-secretase inhibitor nirogacestat for patients with progressive desmoid fibromatosis is ongoing (NCT03785964), and, if positive, may provide yet another novel systemic option for patients.
A clearer understanding of the natural history and pathophysiology of DTs has evolved over the last decade, which has influenced the therapeutic approach. Although aggressive, upfront surgical resection was historically recommended for all DTs, newer systemic agents and improved techniques in RT provide excellent local control for these locally aggressive tumors. Surgical intervention is warranted for symptomatic tumors or tumors that are threatening function but should only be considered after multidisciplinary discussion.
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- Janssen ML, van Broekhoven DL, Cates JM, et al. Meta-analysis of the influence of surgical margin and adjuvant radiotherapy on local recurrence after resection of sporadic desmoid-type fibromatosis. Br J Surg. 2017;104(4):347-357.
- Von Mehren M, Benjamin RS, Bui MM, et al. NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, Version 2.2016. J Natl Compr Canc Netw. 2016;14(6):758-786.
- Briand S, Barbier O, Biau D, et al. Wait-and-see policy as a first-line management for extra-abdominal desmoid tumors. J Bone Joint Surg Am. 2014;96(8):631-638.
- Fiore M, Rimareix F, Mariani L, et al. Desmoid-type fibromatosis: A front-line conservative approach to select patients for surgical treatment. Ann Surg Oncol. 2009;16(9):2587-2593.
- Kasper B, Baumgarten C, Garcia J, et al. An update on the management of sporadic desmoid-type fibromatosis: A European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG). Ann Oncol. 2017;28(10):2399-2408.
- Guadagnolo BA, Zagars GK, Ballo MT. Long-term outcomes for desmoid tumors treated with radiation therapy. Int J Radiat Oncol Biol Phy. 2008;71(2):441-447.
- Bishop AJ, Zarzour MA, Ratan R, et al. Long-term outcomes for patients with desmoid fibromatosis treated with radiation therapy: A 10-year update and re-evaluation of the role of radiation therapy for younger patients. Int J Radiat Oncol Biol Phys. 2019;103(5):1167-1174.
- Bates JE, Morris CG, Iovino NM, et al. Radiation therapy for aggressive fibromatosis: The association between local control and age. Int J Radiat Oncol Biol Phys. 2018;100(4):997-1003.
- Schmitz JJ, Schmit GD, Atwell TD, et al. Percutaneous cryoablation of extraabdominal desmoid tumors: A 10-year experience. AJR Am J Roentgenol. 2016;207(1):190-195.
- Havez M, Lippa N, Al-Ammari S, et al. Percutaneous image-guided cryoablation in inoperable extra-abdominal desmoid tumors: A study of tolerability and efficacy. Cardiovasc Intervent Radiol. 2014;37(6):1500-1506.
- Redifer Tremblay K, Lea WB, Neilson JC, King DM, Tutton SM. Percutaneous cryoablation for the treatment of extra-abdominal desmoid tumors. J Surg Oncol. June 24, 2019 [Epub ahead of print]. Available at: https://onlinelibrary.wiley.com/doi/abs/10.1002/jso.25597. Accessed August 20, 2019.
- Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018;379(25):2417-2428.
- Toulmonde M, Ray-Coquard IL, Pulido M, et al. DESMOPAZ pazopanib (PZ) versus IV methotrexate/vinblastine (MV) in adult patients with progressive desmoid tumors (DT): A randomized phase II study from the French Sarcoma Group. J Clin Onc. 2018;36(15):11501.
- Gega M, Yanagi H, Yoshikawa R, et al. Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol. 2006;24(1):102-105.
- Patel SR, Evans HL, Benjamin RS. Combination chemotherapy in adult desmoid tumors. Cancer. 1993;72(11):3244-3247.