DT/DF have a highly variable clinical presentation and natural history. There are no standard first-line systemic therapies in DT/DF as only few agents have been examined prospectively and there are no randomized studies. In this cohort, median PFS rates were not reached. Only one patient (with Gardner syndrome) had progressive disease and died. Since desmoid tumors may have a relatively indolent course, we submit that overt radiological response rate and symptomatic improvement may be better primary endpoints for outcome than PFS for clinical trials. Any response must also take into account the occasional patient with spontaneous regressions or delayed regressions from prior therapy.
The most striking aspect of this study is the rapid clinical benefit seen in 16/22 (~70%) of symptomatic patients. Clinical improvement was typically noted within 2 weeks of starting sorafenib; we had not observed such clinical benefit with imatinib. It is notable that radiological benefit (RECIST CR+PR+SD) were most common in extremity DT/DF rather than intra-abdominal tumors (p=0.03, t-test). There was no difference in radiological benefit when sorafenib was first-line or second-line treatment (p=0.9). These findings suggest the response of DT/DF to sorafenib is a function of their biology, i.e. APC
mutation (Gardner syndrome) for intra-abdominal desmoids(17
) versus β-catenin mutation commonly observed in other DT/DF(19
). Conversely, it is difficult to ascribe anti-angiogenic effects of sorafenib as directly responsible for the observed benefit. To date, there are no biomarkers that inform natural outcome or clinical benefit with therapies. Tumor or serum levels of KIT, PDGFR, PDGF-AA, PDGF-BB, and CTNNB1
mutation status have not correlated with responses to TKI therapy(14
). Research is underway to elucidate why non-abdominal desmoids respond more frequently to sorafenib than mesenteric desmoids, which may also point to the potential durability of response once treatment has been interrupted.
The optimal imaging modality to evaluate DT/DF remains undefined. Six of 24 patients experienced a RECIST PR and 7/24 had minor tumor shrinkage (10–29%) that represent a response using the alternative response criteria developed by Choi for GIST(20
). Focusing more on the MRI characteristics of desmoids, studies that evaluated soft tissue tumors noted that differences in MRI characteristics are related to the ratio of fibroblasts to collagen(21
). We observed that sorafenib leads to T2 signal loss in 12/13 (~90%) patients, which is suggestive of a shift in fibroblast to collagen ratio. T2 signal loss was observed in all patients with a RECIST PR. Whether T2 signal represents a biological effect is a question for prospective trials with endpoints evaluating quality of life, pre- and post-treatment pathology and time to relapse.
Quantitating MRI T2 signal intensity may be a novel radiographic metric in DT/DF. Stacchiotti et al showed that T1 signal on contrast enhanced MRI may be a novel radiologic marker of response in high grade sarcomas treated with neoadjuvant chemotherapy/radiation(22
). In contrast to computed tomography, in which Hounsfield units may be used as a metric of tissue density, MRI T2 signal is a unitless number with no intrinsic meaning except for comparative purposes. In attempting to develop a reproducible metric for clinical improvement we normalized the signal intensity of lesions by using normal muscle as a reference standard. In this analysis, MRI scans were not performed with identical parameters, which are expected to cause variation in the measured T2 signal intensity, even with a reference standard. In addition, we used a region of interest (ROI) on one representative section which introduces sampling error. In these patients, the changes in signal were homogenous when they did occur, and, thus, our measurements were arguably representative of the entire lesion. The above limitations argue for a prospective study to further evaluate this metric.
Despite our attempt to capture all treated patients, the retrospective nature of this study exposes it to selection bias, as well as possible lead-time bias related to variable imaging intervals. Nonetheless, the relative rapidity of the clinical and radiological responses was striking and appeared to be in excess of what has been reported with other systemic agents, at least as pertains to desmoids not associated with Gardner syndrome. Our clinical observations are supportive of a prospective, randomized trial comparing sorafenib to other active agents, and hopefully provide an otherwise underappreciated means to manage disease in difficult anatomic locations