Clinicopathologic features of the 69 patients are shown in .
Clinicopathologic characteristics of 69 patients with myxofibrosarcoma
All patients underwent surgical resection. Fifty-six patients (81 %) underwent radical resection, 11 (16 %) wide excision, and 2 (3 %) amputation. Thirty-one patients (45 %) underwent complex surgical reconstruction, including a pedicled local flap with or without a split thickness skin graft in 19 patients (28 %), a free flap with microvascular anastomosis in 1 patient (1 %), a split thickness skin graft alone in 8 patients (12 %), and complex primary closure in 2 patients (3 %).
Fifty-three patients (77 %) received RT, including 11 patients with R1 resection (3 patients with grade 1 tumors and 8 patients with grade 2 or 3 tumors) and 42 patients with R0 resection. Of these 53 patients, 5 (9 %) had grade 1 tumors, 13 (25 %) had grade 2 tumors, and 35 (66 %) had grade 3 tumors. Preoperative RT was administered in 32 patients (60 %), postoperative RT was provided in 8 patients (15 %), and 13 patients (25 %) received both pre- and postoperative RT. Of these 13 patients, 2 received intraoperative electron-beam radiotherapy and 11 patients received postoperative external-beam radiotherapy boost doses from 10 to 20 Gy to the tumor bed. Examining the 46 patients who received preoperative treatment, 30 (64 %) received a total preoperative dose of 50 Gy. Eight patients (12 %) received interdigitated preoperative chemoradiotherapy with 44 Gy over 2 divided fractions. Two patients received preoperative RT doses of 20 and 22 Gy, respectively. The former patient received 20 Gy RT before definitive surgery after a previous knee arthroscopy introduced possible intra-articular contamination with tumor cells. The latter patient received 22 Gy in hospital before definitive surgery.
Of the patients who received solely postoperative RT, 7 patients received doses between 60 and 68 Gy, and 1 patient received a 14 Gy boost to the tumor bed after a R0 resection. The latter patient had a 13-cm grade 2 tumor, but because of advanced age, this patient could only tolerate a short RT course. Specifically looking at patients with grade 2 and 3 tumors who received R1 resections (8 patients), 7 patients received preoperative RT with 50 Gy, and 5 received additional postoperative RT for positive margins (range 10–20 Gy).
Receipt of radiation based on tumor grade and surgical margin status is shown in .
Number of myxofibrosarcoma patients receiving radiation (N = 53) based on margin status and grade
Thirteen patients (18 %) received chemotherapy, including 11 (16 %) who underwent combined pre- and postoperative chemotherapy. Three patients (4 %) with grade 1 tumors, 4 (6 %) with grade 2 tumors, and 6 (9 %) with grade 3 tumors received chemotherapy. The most common chemotherapy regimen (7 patients) was MAID (mesna, Adriamycin, ifosfamide, dacarbazine). One patient received preoperative bevacizumab in combination with RT (50.4 Gy) on a phase II clinical trial.
Kaplan–Meier estimates for OS and LRFS are shown in . At a median follow-up of 41 months (range 2–161 months), 19 patients (28 %) had died, 46 patients (67 %) were alive without evidence of local or distant recurrence, and 4 patients (6 %) were alive with locally recurrent or metastatic disease. The 5-year OS rate was 61 %, while the 5-year LRFS, DRFS, and overall RFS rates were 72 %, 82 %, and 62 %, respectively. None of the patients with grade 1 tumors experienced local or distant recurrence.
a Kaplan–Meier curve for overall survival. b Kaplan–Meier curve for local recurrence-free survival
For high-grade (grades 2 and 3) patients only, the 5-year OS was 53 %, while the LRFS, DRFS, and overall RFS rates were 66 %, 80 %, and 58 %, respectively.
Age (hazard ratio [HR] 1.80, P = 0.002), scaled by 0.1, and tumor size (HR 1.12, P = 0.004), modeled as a continuous variable, were univariately significant predictors of worsened OS. A trend was seen toward decreased OS for higher tumor grade patients (HR 2.03, P = 0.069), while a favorable trend was seen for patients receiving RT (HR 0.46, P = 0.100). Age and tumor size were found to be independently significant on multivariate analysis (both P < 0.01); however, this multivariate model was considered exploratory as a result of the modest sample size and low event rate.
For high-grade patients only, age (HR 2.64, P = 0.039), scaled by 0.1, and tumor size (HR 1.11, P = 0.010) again univariately predicted worsened OS.
Local recurrence occurred in 11 patients (16 %) at a median of 16 months (range 6–85 months) after diagnosis. Nine of these patients (82 %) experienced recurrence within 36 months of the initial diagnosis. Clinical courses of these patients are shown in . Treatment for these locally recurrent tumors included surgery alone in 4 patients (6 %), surgery and RT in 4 patients (6 %), and surgery and brachytherapy in 2 patients (3 %). One patient underwent definitive external-beam RT with complete tumor regression. Four patients (6 %) experienced multiple local recurrences.
Tumor characteristics and treatment courses for 11 patients with local recurrence
Looking specifically at patients with high-grade tumors, local recurrence occurred in 8 patients (12 %) with grade 3 tumors and 3 patients (4 %) with grade 2 tumors, including 1 patient whose tumor grade increased from 2 to 3 upon recurrence. Of the 8 patients with grade 3 tumors, 3 had negative surgical margins, 1 had a close margin, and 4 had positive margins. Of the 3 patients with grade 2 tumors, 2 had had close margins and 1 had a positive margin.
Close/positive margin status (HR 4.34, P = 0.030) was the sole significant predictor of local recurrence on univariate analysis, while R status (HR 3.08, P = 0.064) showed a trend toward significance. There were no univariately predictive variables of local recurrence when considering high-grade patients alone.
Distant metastatic disease occurred in 11 patients (16 %) at a median of 10 months (range 3–64 months) after diagnosis, including 3 patients (4 %) who also developed local recurrences. Distant recurrence occurred in 8 patients (12 %) with grade 3 tumors and 3 patients (4 %) with grade 2 tumors. Only one patient who had a documented grade of the metastatic site had an increase in the grade of his disease from 2 to 3. Of those who developed distant metastases, 4 patients (6 %) developed metastases at multiple sites. Ten patients (15 %) developed lung metastases, and 4 underwent surgical metastasectomy. Four patients (6 %) developed brain metastases, 2 of whom underwent surgery with whole-brain RT and 2 of whom received chemotherapy alone. Other sites of metastases included small bowel, pelvis, retroperitoneum, stomach, liver, and adrenal gland. Chemotherapeutic regimens provided after the development of metastases varied widely and included gemcitabine/docetaxel, vinorelbine, liposomal doxorubicin, ifosfamide/etoposide, trabectedin, MAID, gemcitabine/vinorelbine, and Adriamycin.
Tumor size (HR 1.16, P = 0.004) and receipt of chemotherapy (HR 3.50, P = 0.048) were the only univariately significant predictors of distant metastatic disease, while tumor location (lower extremity vs. remaining sites, HR 4.43, P = 0.057) and tumor grade (HR 2.92, P = 0.106) trended toward significance (). An exploratory multivariate analysis considering all four of these variables, and stepwise selection showed that only tumor size maintained significance in the multivariate setting (P < 0.01). Only tumor size (HR 1.15, P = 0.009) persisted as a univariately significant variable when considering high-grade tumors alone.
Univariate analysis of prognostic factors