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Originally published as JCO Early Release 10.1200/JCO.2005.03.6566 on December 5 2005 © 2006 American Society of Clinical Oncology.
Desmoid Tumors Respond to Chemotherapy: Defying the Dogma in OncologyThe University of Texas M.D. Anderson Cancer Center, Houston, TX Desmoid tumors, also known as deep or aggressive fibromatoses, are low-grade mesenchymal neoplasms that fall within the spectrum of a variety of benign musculoaponeurotic fibromatoses but have a tendency to have a high degree of local infiltration and invasion. The true etiology is unknown; however, genetic predisposition in patients with familial adenomatous polyposis (FAP) and estrogenic influence as a result of its association with pregnancy have been implicated. Desmoid tumors do not dedifferentiate to a high-grade malignancy and do not metastasize. Consequently, in the extremely rare instance when a patient presents with multiple discontiguous lesions throughout the body, it is thought of as multifocal disease. Desmoid tumors are generally classified as intra- or extra-abdominal. The extra-abdominal tumors, which are usually sporadic in nature, are effectively treated with local therapy including margin-negative surgery with or without radiation therapy. Radiation therapy alone has also been reported to be beneficial as primary therapy.1 Local recurrences tend to be a problem when adequate surgical resection is not feasible or is not accomplished. Patients who have multiple locoregional recurrences despite adequate local therapy are considered for systemic therapy. Additional indications for systemic therapy include unresectable tumors and intra-abdominal desmoids, especially the tumors associated with FAP and Gardner’s syndrome. The latter variant is characterized by diffuse infiltration of the mesentery and its vasculature, which, therefore, renders the process unresectable. However, a more important reason to avoid surgery in this setting is the clinical observation that recurrences tend to become more frequent and aggressive with each surgical intervention. Options for systemic therapy include anti-inflammatory agents (such as indomethacin and sulindac), hormonal agents (such as antiestrogens and androgens), systemic chemotherapy, and investigational agents (most recently, imatinib mesylate). The dogma prevalent in medical oncology has been that low-grade tumors with no known metastatic potential do not kill patients and should not respond to chemotherapy. Desmoid tumors, especially when associated with FAP, defy this dogma on both counts. These tumors are responsible for death in up to 11% of these patients, second only to colorectal carcinoma.2 Therefore, it is important to treat appropriate patients early and aggressively with systemic therapy to avoid life-threatening complications. Clinical situations without any impending threat to life or function are usually treated with less toxic approaches, such as hormonal therapy. Tamoxifen is the most commonly used agent, with some suggestion that higher doses (up to 120 mg/d) in combination with anti-inflammatory agents are more effective than tamoxifen alone.3 In general, the true regression rate with tamoxifen is in the 15% to 20% range, with another 25% to 30% of patients achieving symptomatic improvement with stabilization of disease, resulting in a clinical benefit rate of up to 50%. Typically, these tumors are slow to manifest actual reduction in size. Not infrequently, shrinkage lags behind discontinuation of therapy by months or even years, raising the possibility that the mechanism of action may well be deprivation of the growth signal or cytokine, which results in prolonged and continued regression long after discontinuation of the therapy. This phenomenon has been noted with radiation therapy, hormonal therapy, and systemic chemotherapy. In this issue, Gega et al4 report their experience with a 96-hour continuous infusion of doxorubicin and dacarbazine followed by oral meloxicam in seven patients with symptomatic, unresectable, FAP-associated desmoid tumors. Three patients achieved a complete response, and the other four patients achieved a partial response; the progression-free survival time was 74 months.4 This is in keeping with our experience with a similar regimen showing definite activity reported in 1993.5 Other investigators have also reported activity with other doxorubicin-based regimens, methotrexate and vinblastine, vinorelbine, and other agents.6,7 In all cases, durable responses lasting years have been reported, clearly establishing the efficacy of systemic chemotherapy in this disease. Because of the toxicity profile of systemic chemotherapy, appropriate patient selection is of paramount importance.
The addition of an anti-inflammatory agent (in this instance, meloxicam, a cyclooxygenase-2 inhibitor) is an interesting concept. Although the true value of this class of drugs in addition to chemotherapy can only be determined in a randomized trial, the wisdom of such an endeavor in a rare tumor like the desmoid tumor is open to debate. Nevertheless, the theoretical advantage of the cyclooxygenase-2 inhibitors blocking MDR-1 overexpression, in addition to the possible antivascular, anti-invasive, and proapoptotic activity, lends credence to a formal phase II trial to better assess efficacy and toxicity of such an approach. Desmoid tumors have been shown to express KIT and PDGFR. Anecdotes of responses to the orally administered kinase inhibitor imatinib mesylate have been reported. On the basis of this rationale, the Sarcoma Alliance for Research through Collaboration is currently conducting a phase II study of imatinib mesylate at a dose of 300 mg twice daily. Preliminary data presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004, reported 2- and 4-month progression-free survival rates of 91% and 78%, respectively. Polymorphisms/mutations of PDGFR- Finally, the notion that a specific genotype can predict the development of an aggressive desmoid tumor in a given patient could prove to be valuable in allowing appropriate patient selection for early therapy or even a chemopreventive strategy. Sites of mutation in the adenomatous polyposis coli (APC) gene have been reported to correlate with age of onset, severity of colonic polyposis, and extracolonic manifestations in patients with FAP. Mutations in codon 1309 correlate with earlier onset of disease compared with other mutations between codons 168 and 1580. Likewise, a higher incidence of desmoid tumors has also been reported by this same group in patients with mutations between codons 1445 and 1580 in the APC gene.9 However, the clinical significance of this finding and the practical utility of this test for therapeutic decision making remain to be established. In summary, desmoid tumors are low-grade neoplasms with locally aggressive behavior. Extra-abdominal desmoid tumors can generally be treated effectively with local therapy; however, intra-abdominal variants, especially the ones associated with FAP, can be potentially lethal and frequently require systemic therapy. Combination chemotherapy may be highly effective in achieving significant and durable cytoreduction, obviating the need for any surgical intervention, which tends to be counterproductive in this group of patients. Continued efforts at improving the efficacy of such regimens with possible additions of anti-inflammatory or antivascular agents should be studied in phase II trials. Prospective evaluation of better predictive factors and chemopreventive strategies in the high-risk population also needs to be pursued in controlled clinical trials. Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
REFERENCES
1. Ballo MT, Zagars GK, Pollack A, et al: Desmoid tumor: Prognostic factors and outcome after surgery, radiation therapy or combined surgery and radiation therapy. J Clin Oncol 17:158-167, 1999 2. Arvanitis ML, Jagelman DG, Fazio VW, et al: Mortality in patients with familial adenomatous polyposis. Dis Colon rectum 33:639-642, 1990[CrossRef][Medline] 3. Hansmann A, Adolph C, Vogel T, et al: High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer 100:612-620, 2004[CrossRef][Medline] 4. 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 24:102-105, 2006 5. Patel SR, Evans HL, Benjamin RS: Combination chemotherapy in adult desmoid tumors. Cancer 72:3244-3247, 1993[CrossRef][Medline] 6. Weiss AJ, Horowitz S, Lackman RD: Therapy of desmoid tumors and fibromatosis using vinorelbine. Am J Clin Oncol 22:193-195, 1999[CrossRef][Medline] 7. Okuno SH, Edmonson JH: Combination chemotherapy for desmoid tumors. Cancer 97:1134-1135, 2003[CrossRef][Medline] 8. Baker LH, Wathen K, Chugh R, et al: Activity of imatinib mesylate in desmoid tumors: Interim analysis of a SARC phase 2 trial. J Clin Oncol 22:821s, 2004 (suppl; abstr 9013) 9. Friedl W, Caspari R, Sengteller M, et al: Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut 48:515-521, 2001
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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exon 18 have been noted. Fifty patients have been accrued to that trial, observation continues, and mature data is awaited.
