For patients with advanced desmoid tumors that are not amenable to surgery or radiotherapy, or if surgery is potentially mutilating, various medical treatment options have been investigated, although generally not in a controlled clinical trial setting. These include antihormonal therapies, NSAIDs, targeted therapies, and traditional cytotoxic chemotherapies. Responses are seen only in a subset of patients, and there have been no markers yet identified being predictive for response. Furthermore, response evaluation according to the conventional Response Evaluation Criteria in Solid Tumors (RECIST) may be difficult in a tumor that can have spontaneous growth arrest and variable growth patterns.
The use of antihormonal therapy for the treatment of desmoid tumors is based on observations of the natural history of the disease. Certain observations, for example, higher incidences of desmoids during and after pregnancy and reports of spontaneous tumor regression after menopause, form the basis for antihormonal therapy. Studies have shown that virtually all desmoid tumors express nuclear estrogen receptor-β, but only a small subset of patients respond to antihormonal therapies [35
]. One of the most commonly used antiestrogens in desmoid tumors is tamoxifen, with many citations in the literature excellently reviewed by Janinis et al. [5
]. However, most of these reports were single case reports demonstrating some sort of response or disease stabilization. Larger series of patients are not available; therefore, no firm conclusion regarding the effectiveness of tamoxifen against desmoids can be reached. It was reported, in a nonrandomized setting, that high-dose tamoxifen (120–200 mg/day) may be more effective than lower doses of 10–40 mg/day [36
]. However, there is no randomized data supporting the use of high doses of tamoxifen, and the risk for second cancers and deep venous thrombosis could be greater with its use.
The use of NSAIDs against aggressive fibromatosis initially was based on the surprising observation of total regression of a single desmoid tumor of the sternum in a patient taking indomethacin for radiation-induced pericarditis [37
]. Because COX-2 seems to play a role in the pathogenesis of desmoid tumors, treatment with NSAIDs that inhibit COX may be effective. Moreover, NSAIDs demonstrate influence on the β-catenin pathway [38
]. A variety of NSAIDs, such as indomethacin and sulindac, a long-acting analog of indomethacin, were tested in the treatment of desmoid tumor patients and were associated with partial and complete responses in several nonrandomized retrospective studies, either alone or in combination with hormonal agents such as tamoxifen. These different studies are also excellently reviewed by Janinis et al. [5
]. The overall response rate of patients treated with sulindac is ~50%, and the majority of responders experienced a delayed response with a mean time of 24 months. Therefore, administration of sulindac with or without tamoxifen seems to be an effective noncytotoxic drug treatment that has, however, not been proven through a randomized comparison [36
]. In a series of 25 patients, this combination was used as a first-line treatment, and all three patients with sporadic desmoids and 10 of 13 patients with FAP-associated disease developed stable disease, a partial response, or a complete response [36
]. Because of its low toxicity, endocrine and/or NSAID therapy is usually considered first-line medical treatment for unresectable, advanced disease without clinical symptoms.
In contrast, in cases of an unresectable, rapidly growing and/or symptomatic and/or life-threatening desmoid tumor, traditional cytotoxic chemotherapy may be the treatment of choice. gives an overview of selected chemotherapy regimens used for desmoid tumor patients with advanced disease. In summary, weekly administration of methotrexate and vinblastine has been evaluated mainly in the pediatric patient population and has reasonable activity with tolerable toxicity. The largest series showed at least stable disease in 18 of 27 patients, with eight of 27 patients being free from progression at a median of 43 months [39
]. However, it has been questioned whether this regimen can also be applied safely in adults because the combination of vinblastine and methotrexate is quite toxic over time and patients generally cannot complete the recommended year of therapy [40
]. Alternatively, the combination of vinorelbine and methotrexate can be administered and is likely much less toxic. There is greater benefit from anthracycline-based therapy [41
] (compare ), and anthracyclines and hormonal therapy appeared to be the most active agents in the series of de Camargo et al. [43
]. More recently, pegylated liposomal doxorubicin at a dose of 50 mg/m2
every 4 weeks was reported to have significant activity, with four of 12 objective responses and seven cases of stable disease according to the RECIST, and with acceptable toxicity. Nevertheless, six of 11 patients required dose reduction of liposomal doxorubicin because of toxicity [44
]. Pegylated liposomal doxorubicin is therefore considered the treatment of choice by many investigators. However, the dose of 50 mg/m2
every 4 weeks is too toxic for most patients, so dose reductions are appropriate for patients with toxicity, especially when the approach is to give therapy to a maximum response, which can take 12–18 months or even longer.
Possible chemotherapy regimens for desmoid tumor patients with advanced disease
Locoregional chemotherapy in the form of isolated limb perfusion is another alternative to systemic chemotherapy in patients with limb desmoids, which is particularly interesting if one considers that desmoid tumors rarely form metastases. Melphalan and recombinant human tumor necrosis factor-α are used as therapeutic agents with overall response rates of up to 80%. Characteristically, intratumoral hypervascularity disappears after perfusion rather rapidly; however, it may take several weeks to months until a partial or complete response develops. This method seems to be especially useful for patients with locally advanced or recurrent tumors not amenable to function-preserving resections [45
Targeted therapies such as imatinib have also been investigated, and both objective remissions and disease stabilization have been reported. Initial data on the use of imatinib in patients with desmoid tumors showed a response in two patients with extra-abdominal fibromatosis [47
]. In contrast to other imatinib-responsive tumors, for desmoids it is uncertain whether or not the response is a result of inhibition of known imatinib targets such as KIT, ABL, ARG, and PDGFR-A and PDGFR-B kinases. In chronic myeloid leukemia or GIST, specific genomic mutations and chromosomal translocations have been demonstrated. No such genomic changes have been observed for desmoids, showing that the response to imatinib is not attributable to Kit expression [48
]. Heinrich et al. [49
] treated 19 patients with desmoid tumors with 800 mg imatinib daily. Three partial responses and four patients with disease stabilization were observed. Genomic analyses revealed no mutations in KIT
, or PDGFR-β
. The authors reported that a drop in serum values of PDGF-β was observed in patients responding to imatinib treatment. Two further reports showed promising results: Penel et al. [50
] were able to demonstrate a 3% complete response rate, 9% partial response rate, and 83% stable disease rate in 40 patients with relapsed or refractory desmoid tumors. The 6-month progression-free survival rate was 74% and the 12-month progression-free survival rate was 69% [50
]. These findings from the French Sarcoma Group were updated recently with a 2-year progression-free survival rate of 55% and a 2-year overall survival rate of 95%. Interestingly, none of the biological factors tested in that study, including PDGFR-α and PDGFR-β, β-catenin, KIT, and cyclin D1 were correlated with response, progression-free survival, or overall survival [51
]. Chugh et al. [52
] observed similar promising response rates and nonprogression rates in 51 patients. However, the objective response rate was low and disease progression at enrollment was not required.
Imatinib is not yet licensed for use for this indication, and this is still a matter of current research. The RECIST response rate for imatinib is <10% and therefore much lower than that of traditional chemotherapy or hormonal therapy. Given its expense and low response rate, it should be reserved for when other options have failed. Finally, the clinical impact of imatinib in the treatment of desmoid tumors can only be evaluated prospectively. Currently, a trial of the German Interdisciplinary Sarcoma Group is studying the role of imatinib and nilotinib in a clinical phase II study to evaluate the induction of progression arrest in patients with aggressive fibromatosis/desmoid tumors with documented progression and not amenable to surgical R0 resection or accompanied by unacceptable function loss (EUDRACT: 2007–000624-40, ClinicalTrials.gov identifier, NCT01137916) [53
Preliminary data on the use of sorafenib in 17 evaluable desmoid tumor patients have been presented, with six of 17 (35%) patients with a partial response, ten of 17 (58%) patients with stable disease, and one patient with progressive disease and death. Improvement in terms of pain and mobility was observed in 65% of patients [54
To evaluate the efficacy of targeted therapies such as imatinib in desmoid tumors, 2-deoxy-2-[18
F] fluoro-D-glucose positron emission tomography (PET) may be useful. In a pilot study, nine patients with progressive disease from a desmoid tumor receiving 800 mg of imatinib daily were studied [55
]. Patients were examined with PET prior to the onset of therapy and during imatinib treatment. Seven of nine patients demonstrated stable disease and two patients showed progressive disease according to the RECIST. The 6-month progression-free survival rate for all patients was 67%. A 27% decrease in the median average standardized uptake value (SUV) of the sequential PET examinations was demonstrated, with three patients demonstrating a ≥48% SUV decrease; no patient demonstrated a substantial increase in SUV. With further confirmation of these results, sequential PET imaging may serve as a surrogate marker allowing the detection of SUV changes after imatinib induction, helping to decide whether treatment should be continued or not [55
]. However, given the low response rate with imatinib in patients with desmoid tumors, it is also possible that imatinib merely decreases glucose transporters as a biomarker for drug absorption independent of drug activity. Other limitations of PET scanning in this patient population are the high cost and exposure to radiation. shows an example of PET imaging providing additional information over that with conventional computed tomography or magnetic resonance imaging. Imatinib apparently leads to a decrease in tumor cell activity and therefore stabilization of tumor growth. For desmoids, substantial benefit means progression arrest for most patients. PET imaging could therefore be used to monitor the efficacy of imatinib or other tyrosine kinase inhibitors in patients with desmoid tumors.
Figure 4. Case of a 19-year-old male with a desmoid of the thoracic/abdominal wall, diagnosed in 2007, treated preoperatively with imatinib 800 mg daily. FDG-PET showed a decrease of the average standardized uptake value (SUV) from 3.3 and of the SUVmax from 5.5 (more ...)