Radiosensitivity Translates Into Excellent Local Control in Extremity Myxoid Liposarcoma

Radiosensitivity Translates Into Excellent Local Control in Extremity Myxoid Liposarcoma
Original Article

       Radiosensitivity Translates Into
       Excellent Local Control in Extremity
       Myxoid Liposarcoma
       A Comparison With Other Soft Tissue Sarcomas

       Peter W. M. Chung, MB, ChB1,6; Benjamin M. Deheshi, MD2,3,6; Peter C. Ferguson, MD2,3,6;
       Jay S. Wunder, MD2,3,6; Anthony M. Griffin, MSc3; Charles N. Catton, MD1,6; Robert S. Bell, MD2,3,6;
       Lawrence M. White, MD5,6; Rita A. Kandel, MD4,6; and Brian O’Sullivan, MD1,6

         BACKGROUND: Myxoid liposarcoma has been reported to be more radiosensitive compared with other
         soft tissue sarcomas (STS). The authors report the results of multidisciplinary treatment of extremity myx-
         oid liposarcoma compared with a contemporary cohort of other STS subtypes with an emphasis on the
         role of radiotherapy (RT) in improving local control. METHODS: Between 1989 and 2004, 691 patients were
         identified from a prospective STS database who underwent combined management for localized extremity
         STS and were followed for a minimum of 12 months or until death. All patients underwent surgery together
         with pre or postoperative RT, depending on their presenting characteristics and resection margins. Demo-
         graphics and outcomes were compared between patients with myxoid liposarcoma and other STS sub-
         types (other-STS). RESULTS: Of 691 patients, 88 patients had myxoid liposarcoma and 603 had other STS
         subtypes (other-STS). Median age was 48 and 60 years for the myxoid liposarcoma and other-STS groups,
         respectively. Median follow-up was 86 and 61 months, respectively. For myxoid liposarcoma and other-STS
         groups, preoperative RT was used in 57% versus 61% of patients and postoperative RT in 43% versus 39%,
         respectively. The 5-year local recurrence-free survival was 97.7% for patients with myxoid liposarcoma com-
         pared with 89.6% for patients with other-STS tumors (P ¼ .008). High-grade tumors were present in 7%
         and 59% of myxoid liposarcoma and other-STS patients, respectively (P ¼ .0003). Two myxoid liposarcoma
         patients with local recurrence had positive resection margins, whereas only 33% of patients in the other-
         STS group who developed a local recurrence had positive resection margins. No patients with myxoid lipo-
         sarcoma required amputation as primary management, whereas 8 (1.3%) required amputation as primary
         management in the other-STS group. Systemic disease control was superior in myxoid liposarcoma com-
         pared with other-STS patients, with 5-year overall and metastasis-free survival rates of 93.9% versus 76.4%
         (P ¼ .0008) and 89.1% versus 66.0% (P ¼ .0001) respectively. Of 12 myxoid liposarcoma patients with dis-
         tant metastases, 7 appeared in nonpulmonary sites. In comparison, 205 (34%) patients with other-STS
         tumors developed systemic disease but 78% had pulmonary metastases. CONCLUSIONS: Multidisciplinary
         management of extremity STS achieves high rates of local control. Myxoid liposarcoma is associated with

       Corresponding author: Peter W. M. Chung, MB, ChB, Princess Margaret Hospital, Radiation Oncology, 610 University Ave, Toronto, Ontario M5G
       2M9 Canada; Fax: (416) 946-4442;
        Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada; 2Surgical Oncology, Princess Margaret Hospital, Toronto, Ontario, Can-
       ada; 3Division of Orthopaedic Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada; 4Department of Pathology, Mount Sinai Hospital, Toronto,
       Ontario, Canada; 5Medical Imaging, Mount Sinai Hospital, Toronto, Ontario, Canada; 6University of Toronto, Toronto, Ontario, Canada
       Presented, in part, at the 48th Annual Meeting of ASTRO, Philadelphia, Pennsylvania, November 5–29, 2006.
       Received: September 23, 2008; Revised: December 23, 2008; Accepted: December 31, 2008
       Published online: May 26, 2009 V
                                      C 2009 American Cancer Society

       DOI: 10.1002/cncr.24375,

3254                                                                                                                  Cancer           July 15, 2009
Radiosensitivity Translates Into Excellent Local Control in Extremity Myxoid Liposarcoma
Local Control of Myxoid Liposarcoma/Chung et al

  higher rates of local control compared with other STS subtypes, after combined surgery and radiation, sug-
  gesting a particular radiosensitivity that can be exploited to improve oncologic outcome in appropriate
  cases. Cancer 2009;115:3254–61. V C 2009 American Cancer Society.

  KEY WORDS: myxoid liposarcoma, radiotherapy, local control, combined modality therapy, surgery.

Soft tissue sarcomas (STS) of the extremity are a heter-       METHODS AND MATERIALS
ogeneous group of tumors with differing pathologies that       The research ethics board approved this study. From our
clinically behave in a similar fashion. With the exception     prospectively collected institutional database, 691
of certain pediatric and chemotherapy-sensitive histologi-     patients who had surgical treatment and RT at our center,
cal subtypes, surgery plays a predominant role in the local    between 1989 and 2004, for localized extremity STS
management of extremity STS.1 Radiotherapy (RT) has            were identified. Patients were excluded if: chemotherapy
been shown to be an important adjunctive treatment and         was a part of their treatment (n ¼ 75), they had meta-
improves local control rates over those seen with conserva-    static disease at diagnosis, they had either dermatofibro-
tive surgery alone, particularly when ‘wide’ resection mar-    sarcoma protuberans or well-differentiated liposarcoma.
gins cannot be obtained.2,3 Local control in extremity         Patients who underwent initial surgery elsewhere before
STS would be expected to be around 90% overall with            referral, usually in the form of an unplanned exci-
this approach.2                                                sion,13,14 and were referred for definitive management,
      Myxoid liposarcoma is a common variant of liposar-       were included if they were treated with further conserva-
coma and has a characteristic t(12:16) translocation that is   tive surgery and RT at our center. In this setting, the
shared with myxoid/round cell liposarcoma (a higher            ‘management policy’ evolved over time but currently,
grade variant with more aggressive biology4). Myxoid lip-      patients would generally have preoperative RT and re-
osarcoma has a peculiar characteristic of extrapulmonary       excision unless it was anticipated that excision with wide
metastasis5 not commonly seen in other STS subtypes            margins could be achieved and, thus, RT was not likely
but appears to have a relatively favorable prognosis.6,7       to be needed. All patients had their pathology reviewed to
Although some studies have suggested that myxoid lipo-         confirm the diagnosis and subtype of STS. The grade of
sarcoma may be relatively responsive to RT more than           STS was assigned according to a 3-tier system. Myxoid
other types of STS, with high rates of regression and even     liposarcoma patients were assigned a minimum of grade
reports of complete clinical response,8,9 others have          2, and if there was evidence of 5% or more round cell
reported high rates of local relapse overall; but, it is       component within the specimen, then they were assigned
unclear that all appropriate patients received combined        grade 3. Staging included full history and examination
management with surgery and RT in these studies.10,11          together with cross sectional imaging of the extremity
Pitson et al previously demonstrated an objective response     (usually magnetic resonance imaging [MRI]). Thoracic
of myxoid liposarcoma to RT in the preoperative set-           computed tomography (CT) scans were obtained and
ting.12 Thus adjunctive RT might translate into improve-       other imaging was done at the discretion of the clinician.
ment in local control for myxoid liposarcoma patients          Patients with locally recurrent disease and no distant me-
compared with other adult STS subtypes treated in a simi-      tastases were included as long as the intent of manage-
lar manner.                                                    ment was conservative surgery and RT.
      The aim of this retrospective study was to compare             Patients were treated with limb conserving surgical
the outcomes of multidisciplinary treatment of a cohort of     methods whenever possible. RT was used as an adjunct
myxoid liposarcoma patients with a contemporary group          whenever surgical resection could not be achieved with
consisting of other STS subtypes (other-STS) treated in a      wide negative margins (usually defined as a minimum of 2
standardized manner with particular emphasis on the role       cm). Resections were categorized as complete excision
of RT in local control.                                        with microscopic negative margins (R0), excision with

Cancer       July 15, 2009                                                                                         3255
Original Article

microscopic positive margins (R1) or excision with gross       Table 1. Patient and Treatment Characteristics
positive margins (R2). External beam RT was delivered in
                                                               Characteristics             Myxoid      All Other P
the preoperative setting (50 Gy) or postoperatively (60-66                                 Liposarcoma STS
Gy). In some cases, in the setting of positive margins after                               n 5 88      n 5 603
preoperative RT and surgery, a postoperative boost of up                                   No. (%)              No. (%)
to 16 Gy was delivered. The timing of RT evolved over          Median age, y               48 [16, 86]           60 [15, 95]    .0001
the period under study as postoperative RT was more              [minimum, maximum]

commonly delivered up to 1994. From 1994-1997, a               Sex                                                              .25
                                                                 Male                      52 (59)              314 (52)
national randomized clinical trial (NCIC SR2) of pre ver-        Female                    36 (41)              289 (48)
sus postoperative RT was conducted and influenced the          Median size, cm            8.0 [2.5, 36]         7.5 [1, 39.5]   .51
                                                                 [minimum, maximum]
timing of RT for patients who participated in this trial.
Subsequent to this, preoperative RT became more com-           Grade                                                            .0002*
                                                                 1                         0                    84
mon. After treatment, patients were followed on a stand-         2                         82 myxoid alone      161
ard schedule every 3 months to 6 months for the first 3          3                         6 with round cell    358

years (high-grade patients were seen every 3 months), 6        Depth                                                            .65
                                                                 Superficial               13 (15)              105 (17)
monthly until Year 5, and then annually until 10 years. At
                                                                 Deep                      75 (85)              498 (83)
each follow-up visit, physical examination and chest x-ray
                                                               Radiotherapy                                                     .57
were performed, and other imaging was done at the dis-           Preoperative              41 (47)              317 (52.5)
cretion of the physician. Minimum follow-up was 12               Postoperative             38 (43)              234 (39)
                                                                 Preoperative 1             9 (10)               52 (8.5)
months.                                                            Postoperative boost

                                                               Prior surgery (unplanned excision)                               .35
                                                                 No                        58 (66)              362 (60)
Statistical Methods                                              Yes                       30 (34)              241 (40)

Local recurrence-free survival, metastasis-free survival,      Margin status after final surgery                                .34
                                                                 Negative (R0)             71   (81)            459   (76)
and overall survival were estimated using the Kaplan-            Positive (R1)             17   (19)            144   (24)
Meier method. Survival time was calculated from the date         Positive (R2)              0   (0)               7   (1.2)
                                                               Amputation                   0   (0)               8   (1.3)
of definitive surgery for the primary tumor. Differences in
survival were compared using the log-rank test. A p-value
Local Control of Myxoid Liposarcoma/Chung et al

              Table 2. Oncologic Outcomes

              Outcome                                         Myxoid Liposarcoma,               All Other STS,       P
                                                              n 5 88                            n 5 603
                                                              No. (%)                           No. (%)

              Current status
                Alive, no evidence of disease                   73 (83)                            376   (65)
                Alive with evidence of disease                   5 (6)                              73   (11)
                Deceased (nonsarcoma related)                    3 (3)                              35   (6)
                DOD                                              7 (8)                             119   (18)
              5-Year overall survival                         93.9%                             76.4%                .0008

              Local recurrence
                Preoperative radiation                        0/41 (0)                          32/317   (10)
                Preoperative 1 postoperative boost             1/9 (11)                          10/52   (19)
                Postoperative radiation                       1/38 (3)                          18/234   (8)
              5-Year LR-free survival                         97.7%                             89.6%                .008
              Metastases                                        12 (13.6)                          205   (34)
              5-Year metastasis-free survival                 89.1%                             66%                  .0001

              STS indicates soft tissue sarcoma; DOD, dead of disease; LR, local recurrence.

FIGURE 1. Overall survival myxoid liposarcoma versus other                   FIGURE 2. Metastasis-free survival myxoid liposarcoma ver-
STS subtypes (P ¼ .0008).                                                    sus other STS subtypes (P ¼ .0001).

The corresponding RT treatments in the other-STS group                             Overall survival at 5 years (Fig. 1) was 93.9% for the
were 52.5%, 8.5%, and 39%, respectively.                                     myxoid liposarcoma group and 76.4% for the other-STS
                                                                             group (p < .01). Not surprisingly, metastatic disease
                                                                             developed more frequently in patients who were in the
                                                                             other-STS group, in keeping with the larger proportion of
Outcomes                                                                     patients with high-grade disease in that group. Metastasis-
Median follow-up was 86 months for the myxoid liposar-                       free survival at 5 years (Fig. 2) was 89.1% and 66.0% for
coma group and 61 months for the other-STS group. The                        the myxoid liposarcoma and other-STS groups, respec-
main oncological outcomes are shown in Table 2.                              tively (P < .01).

Cancer       July 15, 2009                                                                                                         3257
Original Article

      Overall, 5-year local relapse-free survival was 97.7%      types of STS, and although some historical series reported
for the myxoid liposarcoma group and 89.6% for other-            high rates of local recurrence (up to 33%) in patients
STS patients.                                                    treated with surgery alone,6,19 other small series have
      When patients with locally recurrent disease were          noted good local control with the addition of RT.17,20,21
excluded, local recurrence-free rates were 98% for the           In 1 such study of 10 patients, even in the presence of
myxoid liposarcoma group and 91% for the other-STS               marginal or intralesional excisions without further sur-
group (P ¼ .02) at 5 years.                                      gery, the addition of RT resulted in excellent local control
      Of patients with local recurrence, both in the other-      with no local relapses at mean follow-up of 58 months,
STS group had positive margins (and both patients had            suggesting that the radiosensitivity of the tumor improved
grade 2 disease), whereas 33% (20 of 60) in the other-STS        local control.22 Another more recent series examining
group had positive margins.                                      combined modality therapy reported 100% local control
      Overall, 12 (13.6%) myxoid liposarcoma developed           in 9 patients with positive margins, 99% local control in
metastatic disease and 2 had multiple sites involved             91 patients with negative margins, and only 87% local
including mediastinum, spine, lung, and bone. Of 10              control in 25 patients where the margin status was
myxoid liposarcoma patients who developed a solitary site        unknown.23 In our series, we did not have any patients
of metastatic disease, 4 had pulmonary metastases, 2             with gross positive margins (R2 resections) in the other-
intra-abdominal disease, 3 a soft tissue metastasis, and 1 a     STS group, but there were 7 (1.2%) patients within the
spinal bone metastasis. Subsequently, 6 of these patients        other-STS group who had R2 resections. We were not
developed further metastases. In contrast, of those in the       able to distinguish patients with narrow but microscopi-
other-STS group who developed metastases, 78% (160 of            cally negative margins of excision compared with those
205) had pulmonary metastases.                                   with a more widely negative excision as all were coded as
                                                                 R0. Of myxoid liposarcoma patients in our study, 17
                                                                 had positive margins, of whom only 2 had local recur-
DISCUSSION                                                       rence (compared with 20 of 60 of other-STS patients).
Patients with extremity STS, managed at our center with          Although the local control in myxoid liposarcoma
combined surgery and RT, had excellent local control             patients is excellent, we believe our data confirm the
rates (90%) that compare favorably with other large se-         need for adequate local surgery resulting in negative mar-
ries reported in the literature.15 In a recently published se-   gins whenever possible because only those myxoid lipo-
ries of 279 patients undergoing primary treatment for            sarcoma patients with positive resection margins
STS, the local recurrence rate was reported to be 16%.16         recurred locally.
       Although the myxoid liposarcoma and other-STS                    Although the sensitivity of myxoid liposarcoma to
groups were comparable, the overall 5-year local disease         RT was first reported more than 70 years ago and has
control for patients with myxoid liposarcoma treated with        been described by others,8,24,25 only recently has objective
surgery and RT was exceptional. We hypothesized that the         evidence of this response been reported. Pitson et al com-
radiosensitivity of myxoid liposarcoma would facilitate          pared patients with myxoid liposarcoma to a group with
improved local control in patients treated with combined         malignant fibrous histiocytoma who were both treated
surgery and RT. The results of this study support our            with preoperative RT.12 Using MRI, before and after RT,
theory as myxoid liposarcoma patients treated with (neo)-        a proportional reduction of 59% in median tumor vol-
adjuvant RT had 98% 5-year local control compared with           ume was measured in myxoid liposarcoma patients. The
90% for other-STS patients.                                      mechanism by which this volume reduction occurs is
       Reports of patients with well-differentiated liposar-     unknown but could be due to a particular cellular suscep-
coma, which generally requires surgery alone without RT,         tibility or loss of tumor stroma. The TLS-CHOP (FUS-
and pleomorphic liposarcoma, which may have a higher             DDIT3) translocation, which is commonly present in
rate of local recurrence, even when treated with adjuvant        myxoid liposarcoma, and the resulting fusion protein play
RT, have been included together with myxoid liposar-             a central role in formation of these tumors. These mutant
oma.17,18 Myxoid liposarcoma may be distinct from other          fusion proteins involving CHOP fail to allow growth

3258                                                                                              Cancer        July 15, 2009
Local Control of Myxoid Liposarcoma/Chung et al

arrest in response to radiation and may, thereby, lead to
the radiosensitivity typical of myxoid liposarcoma tumor
cells. It must be noted that while the presence of this trans-
location may aid the diagnosis of myxoid liposarcoma, it
has not been shown, at least thus far, to have prognostic
significance.26 This tendency to respond to RT is not only
important when planning combined treatment, but it
appears to increase the likelihood of local control for myx-
oid liposarcoma compared with other STS subtypes.
       Many of our patients were treated with preoperative
(neoadjuvant) RT, which has been shown to result in the
same level of local control as postoperative (adjuvant) RT
in STS patients.27 An advantage of preoperative RT over
postoperative RT may be to limit late morbidity, particu-
larly in patients with large tumors as the smaller treatment
volumes and lower doses delivered in preoperative RT
may result in better functional outcome with less fibro-
sis28 as well as reduction in risk of bone fracture.29
Although the use of preoperative RT in STS patients has
not been universally adopted, its use in myxoid liposar-
coma patients may be preferable for several reasons. First,
preoperative RT would be expected to cause a large reduc-
tion in tumor volume, which may, in turn, allow less mor-
bid surgery, resulting in improved functional outcomes
without compromising local control. Second, preopera-
tive RT facilitates surgical sparing of critical structures ad-
jacent to the tumor margin. Even in the setting of
‘‘planned’’ positive margins after preoperative RT, where
the tumor does not shrink away from a vital structure after
preoperative RT, for example, after epineural dissection
of a major motor nerve, local control rates do not appear
to be significantly reduced.30 This may be particularly rel-
evant in the setting of myxoid liposarcoma as such tumors
frequently arise in intermuscular locations and may
involve neurovascular bundles.31 An example of the type
of response that may be seen with preoperative RT in
myxoid liposarcoma is shown in Figure 3.
       Patients with myxoid liposarcoma generally have a
good prognosis and have the potential to gain maximum
benefit from strategies that minimize the long-term conse-        FIGURE 3. Axial fat suppressed fast spin-echo T2-weighted
quences of RT. With modern RT techniques, such as in-             (A) MR in a 55-year-old male patient with a myxoid liposar-
                                                                  coma of the posterior compartment of the left thigh (arrows
tensity-modulated radiotherapy, further benefit might be          in A). Corresponding axial fat suppressed fast spin-echo T2-
derived from reducing the normal tissue volume that               weighted (B) MR images show dramatic reduction in the size
                                                                  of the lesion post radiation therapy (arrows in B).
receives high doses while maintaining optimal local con-
trol. This may be advantageous in the preoperative set-
ting, but it may be more applicable in the postoperative

Cancer        July 15, 2009                                                                                            3259
Original Article

setting since limiting the volume of normal tissue exposed             In summary, we found excellent rates of local con-
to the higher doses of RT used with the aforementioned          trol for STS patients treated with surgery and RT. Patients
highly conformal RT techniques might be expected to             with myxoid liposarcoma treated at our center had signifi-
reduce the severity of late toxicity in these patients.32       cantly lower rates of local and distant failure compared
       As with all retrospective data, patient selection sig-   with other STS subtypes. Improved local control in myx-
nificantly influences outcome, as is the case in our 2          oid liposarcoma might well be due to its radiosensitivity,
patient cohorts. One might speculate that including             while a lower rate of metastasis may be a reflection of the
patients with locally recurrent disease may reduce the          relatively low numbers of patients with high-grade disease
apparent local control rate for other-STS patients, espe-       in the myxoid liposarcoma cohort as well as the high rate
cially because this group had a larger proportion of            of local control. It has been recognized that particular sub-
patients with locally recurrent disease at initial presenta-    types of STS may have specific characteristics; myxoid lip-
tion. However, even after excluding these patients, the         osarcoma is 1 such subtype, and the data presented here
local control rate was  90% for the other-STS group.           suggest that its radio-responsiveness translates into excel-
For patients who underwent ‘unplanned’ excision of a            lent local control when RT is appropriately applied.
sarcoma elsewhere with positive margins before referral,
our policy is for further re-excision as these patients are
at significant risk of local recurrence even with the addi-     Conflict of Interest Disclosures
tion of RT. Our group and others have reported high             The authors made no disclosures.
rates (59%) of residual disease following ‘unplanned’
excisions, which provides evidence to support this treat-       References
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Cancer         July 15, 2009                                                                                                      3261
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