Methotrexate and Vinblastine or Vinorelbine Remain Useful Treatments for Desmoid-Type Fibromatosis 30 Years Later.

Palassini and colleagues, in this issue of The Cancer Journal, describe long-term clinical benefit using methotrexate and vinblastine or vinorelbine for treatment of patients with desmoid-type fibromatosis and highlight a number of interesting observations of the disease including tumor response may require many months to develop, may continue or occur after discontinuation of treatment, and may be sustained for years after stopping therapy. This retrospective review includes patients treated and followed up at Istituto Nazionale dei Tumori in Milan, Italy, beginning the same year of the first published article describing clinical experience using methotrexate and vinblastine in patients with desmoid-type fibromatosis by Weiss and Lackman1 in the journal Cancer 28 years ago. Desmoid-type fibromatosis, also referred to as desmoid tumor (term used in remainder of commentary) or aggressive fibromatosis, is a spindle-cell, fibroblastic neoplasm exhibiting an infiltrative pattern of growth into surrounding tissue, but it lacks the ability to metastasize. It arises in children and adults and when it occurs in individuals with familial adenomatous polyposis is usually associated with Gardner syndrome (disorder characterized by presence of adenomatous polyps, desmoid tumors, osteomas, epidermoid cysts, and fibromas). Desmoid tumor most often contains an inactivating mutation in the gene encoding β-catenin (CTNNB1) followed by mutation in the APC gene, both of which result in intranuclear accumulation of β-catenin. Patients affected by desmoid tumor frequently present to medical attention because of pain and an associated mass. When desmoid tumor arises in the neck or extremity, limitation in movement about a joint may develop because of a fibrotic effect on muscle or tendons. Desmoid tumor may also arise in the mesentery and cause abdominal pain, intestinal obstruction, mesenteric ischemia, or ureteral obstruction. Mesenteric desmoid tumor may be lethal from intestinal complications. Desmoid tumor arising outside the mesentery is rarely fatal. Desmoid tumor was managed primarily as a surgical disease for many decades. Because of infiltrative growth into surrounding tissue, wide resection was recommended to completely remove the tumor and reduce risk of local regrowth. In many patients, wide resection of the tumor resulted in long-term morbidity, particularly in cases that arose in the head/neck or extremity. Radiation has successfully palliated or controlled primary or recurrent disease following surgery, but concerns over long-term complications from radiation and risk of radiation-associated malignancy have reduced enthusiasm for use of this modality in younger patients.2 Observations of spontaneous regression and long-term stability of desmoid tumors in the absence of medical intervention have prompted the recommendation by some sarcoma experts of a wait-and-see management approach for a patient with a diagnosis of desmoid tumor if the patient is asymptomatic.3,4 However, medical intervention is indicated if a desmoid tumor is progressively enlarging or causing symptoms. Many different classes of drug including nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase 2 inhibitors, antiestrogens, DNA alkylating agents, antimetabolites, anthracyclines, vinca alkaloids, and receptor tyrosine kinase inhibitors have demonstrated antitumor activity in patients with desmoid tumor. A stepwise approach in drug treatment of desmoid tumor is often followed because treatment may be prolonged for months or years, toxicity of treatment varies widely across the different classes of drug, and a clear winner regarding antitumor activity has not emerged. Despite a better understanding of the molecular alterations occurring in desmoid tumor, the molecular nature of antidesmoid activity of the different classes of agents is not well understood. When drug therapy for desmoid tumor is required, many sarcoma oncologists begin treatment with an NSAID with or without an antiestrogenic agent because of the favorable adverse event profile of the drugs. When this treatment fails to control desmoid growth or palliate symptoms, an alternate drug treatment is used.