Neoadjuvant Imatinib in Advanced Primary or Locally Recurrent Dermatofibrosarcoma Protuberans: A Multicenter Phase II DeCOG Trial with Long-term Follow-up

Discussion

In nonresectable DFSP, three clinical trials have investigated imatinib until now (Table 4; ref. 19). The first pilot study found 100% response (CR/PR) using a dose of 800 mg/d (20). These promising results were followed by two parallel trials combined in a joint report (21). The authors found 43.7% responders (CR/PR) in the European Organization for Research and Treatment of Cancer (EORTC) trial using imatinib 800 mg/d, and 50.0% responders in the Southwest Oncology Group (SWOG) trial using 400 mg/d. These data indicate that a lower imatinib-dosing regimen is adequate to achieve a sufficient clinical response. In resectable DFSP, two trials have been done up to now, one of a French consortium (22) and the presently reported (Table 4). Both studies were designed immediately after the first positive case reports of imatinib in metastatic DFSP, before any of the above mentioned trials in nonresectable DFSP had been published. Both used an intermediate dose of 600 mg/d imatinib, and resulted in 36.0% and 57.1% response (CR/PR), respectively. This obvious difference might probably be due to the varying study designs. The French study required the obligatory surgical removal of the tumor as early as 2 months after imatinib onset. The difference in tumor diameters observed in our present study between week 6 and 12 clearly shows that this time point was set too early to reach an objective response in every DFSP sensitive to imatinib. In contrast, in cases of nonprogression our study protocol allowed long-term treatment until definitive surgery. It is likely, that the response rate of the French trial would have been significantly higher if the preoperative treatment duration would have been prolonged. It should be noted that our study involves a number of heterogeneously distributed parameters like safety margins, disease type namely primary or recurrent disease, and different modes of pretreatment. The inclusion criteria were permissive about these points because we aimed at enrolling as many patients as possible with this rare disease. However, it should be taken into account that these heterogeneities might have influenced the study results, particularly the response rate.

The present study of imatinib in DFSP is the first with a long-term patient follow-up (Table 4). Particularly the rate of tumor relapse during follow-up is an important aspect of this trial because it is unknown if the initial efficacy of the drug later translates into a lower potential of relapse. The French study used wide excision margins, but did not perform a patient follow-up. Therefore, unfortunately, a direct comparison of tumor relapse after wide excision in the French trial and narrow to intermediate excision in the present trial is not possible. However, our assumption that a successful pretreatment with a PDGFRB inhibitor allows smaller surgical margins could not be definitely confirmed, since during long-term follow-up we observed 1 patient with a tumor relapse despite of an initially pronounced response to imatinib and subsequent surgery with tumor-free margins. This recurrent tumor was refractory to newly started imatinib, but could be successfully treated with sunitinib 50 mg/d followed by complete surgery. Later, the patient presented with treatment-refractory metastases to the lung, vertebral bodies, and spinal cord, which led to the death of patient.

To the best of our knowledge, this is the first report of a successful treatment of an imatinib-resistant DFSP with second-line sunitinib. It should be taken into account that the binding capacity of sunitinib to PDGFRB is about 10 times more than that of imatinib (23), presuming a high efficacy of this drug in DFSP although it is lacking approval for this entity.

A recent retrospective multicenter study demonstrated that the recurrence rate of DFSP after tumor-free resection is extremely low (<1%), even without use of Mohs surgery (8). The only two cases of that study showing local recurrences had obtained excisions with tumor-positive margins. These data were confirmed by other groups also reporting very low recurrence rates in DFSP excised with clear margins (24, 25). In the present trial, Mohs surgery was not applied because it is not a common procedure in German clinical routine. Our patient showing a tumor relapse had a myxoid-type DFSP, which is known as a rare DFSP variant revealing the same clinical behavior as classical DFSP, particularly with regard to recurrence and metastasis (26). Notably, this tumor was the largest of our trial. However, it is remarkable that it grew slowly for anamnestically more than 10 years, and started rapid growth acceleration only when secondary resistance developed under imatinib treatment. However, this effect did not translate into morphologic or molecular changes. The tumor recurrence still harbored the COL1A1–PDGFB fusion gene, and the histologic and immunohistochemical characteristics were unchanged; particularly, there was no fibrosarcomatous transformation (Fig. 2D). Also, the recurrent tumor responded to sunitinib, indicating that the PDGFRB pathway was still the driving stimulus in this tumor, and imatinib resistance was probably not due to the activation of alternative signaling pathways.

We observed 25% grade 3 and 4 toxicities using an intermediate imatinib dose of 600 mg/d (Table 4). A similar toxicity was reported in the French trial, indicating that 600 mg/d imatinib is well tolerated, regardless of a short- or long-term regimen. The observed toxicity profile is considerably milder than that of the high-dose regimen used in the EORTC trial (21), which showed 81.3% grade 3 and 4 toxicities. Surprisingly, the toxicity observed in the SWOG trial is of similarly high intensity (21), despite the much lower dose of 400 mg/d. This obvious inconsistency might be explained by the fact that 2 of 8 patients of the SWOG trial were dose escalated to 800 mg/d. With regard to the risks versus benefits of imatinib in patients with DFSP, it is questionable whether the observed decrease in tumor size is worth the high probability of side effects with 25% grade 3 and 4 toxicities, and also the potential risk of transformation to a more aggressive tumor type. These interactions have to be investigated in more detail in future clinical trials.

We performed an extensive analysis of histomorphologic and molecular tumor parameters to identify biomarkers of imatinib response. It should be noted that due to low patient numbers in this study, all biomarker analyses were done on an exploratory, hypothesis-building basis, and need confirmation by future clinical trials. Remarkably, pigmented-type DFSP was associated with nonresponse. This finding is confirmed by the observation of one nonresponsive pigmented-type DFSP in a patient treated in the EORTC trial (21), and strikingly, this patient was the only of 25 study patients showing PD as best response. In our present trial, also the only patient with PD as best response was a pigmented-type DFSP. This interesting observation may be explained by the constitutively high treatment resistance of pigmented tumors. With regard to the COL1A1–PDGFB fusion gene, we observed no stringent association with response. However, it must be recognized that the sensitivity of our detection method might have been insufficient. Patel and colleagues demonstrated that the COL1A1–PDGFB fusion gene could be detected in 96% of DFSP cases so far as the detection method is of high enough sensitivity (27). The authors used multiplex RT-PCR followed by direct sequencing of the amplification product combined with FISH; the same methodology was used in our present study. Patel and colleagues used a set of 18 different COL1A1 primers, whereas in our study even 51 COL1A1 primers were used. However, Patel and colleagues used a sample set extracted from the histopathology archive of a single institution. In contrast, we encountered the difficult conditions of the very heterogeneous quality of biomaterials obtained from 10 different study centers. This might explain the much lower COL1A1–PDGFB detection rate in our study (62.5%) compared with that of Patel and colleagues (96%). During imatinib treatment a clinical response was associated with a decrease in tumor cell density and with the formation of a moderate to strong hyalinic fibrosis. The replacement of tumor cells by hyalinized collagen was previously reported in imatinib-treated GIST (28). Also, Kerob and colleagues described hyalinic fibrosis of imatinib-treated tumors in 19 of 25 patients of their study (22).

With regard to target phosphorylation, we correlated clinical response with PDGFRB activation. So far, the only clinical trial using this strategy was the pilot study of McArthur and colleagues, who analyzed five DFSP cases responding to imatinib and found a throughout weak phosphorylation of PDGFRB (20). In contrast, we found a moderate to strong phosphorylation in all but one investigated DFSP. Strikingly, a strong PDGFRB activation was not necessarily associated with clinical response. Moreover, no significant changes in PDGFRB phosphorylation intensity could be detected during imatinib therapy; particularly there was no decrease of PDGFRB activation in responders. Remarkably, the only patient showing a weak pre-imatinib PDGFRB phosphorylation revealed an immediate tumor progression during imatinib treatment; this was the only patient of the whole study presenting with PD as best response. These results indicate that moderate to strong PDGFRB activation is a common event in DFSP and does not necessarily translate into clinical response to imatinib. Nevertheless, a weak PDGFRB phosphorylation seems to be associated with nonresponse. The moderate to strong activation of other RTKs, particularly of EGFR and insulin receptor detected in 100% of the investigated cases, indicates that these RTKs might be interesting candidates for other than PDGFRB directed–targeted therapies of DFSP.