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Excellent Local Control Rates and Distinctive Patterns of Failure in Myxoid Liposarcoma Treated With Conservation Surgery and Radiotherapy
Int. J. Radiation Oncology Biol. Phys., Vol. 70, No. 3, pp. 760–765, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2007.07.2337
CLINICAL INVESTIGATION
Sarcoma
EXCELLENT LOCAL CONTROL RATES AND DISTINCTIVE PATTERNS OF FAILURE IN MYXOID LIPOSARCOMA TREATED WITH CONSERVATION SURGERY AND RADIOTHERAPY B. ASHLEIGH GUADAGNOLO, M.D., M.P.H.,* GUNAR K. ZAGARS, M.D.,* MATTHEW T. BALLO, M.D.,* SHREYASKUMAR R. PATEL, M.D.,y VALERAE O. LEWIS, M.D.,z ROBERT S. BENJAMIN, M.D.,y x AND RAPHAEL E. POLLOCK, M.D., PH.D. Departments of *Radiation Oncology, y Sarcoma Medical Oncology, z Orthopaedic Oncology, and x Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Purpose: To evaluate the local control rates and patterns of metastatic relapse in patients with localized myxoid liposarcoma treated with conservation surgery and radiotherapy (RT). Patients and Methods: Between 1960 and 2003, 127 patients with non-metastatic myxoid liposarcoma were treated with conservation surgery and RT at our institution. The median patient age was 39 years (range, 14–79 years). Of the 127 patients, 46% underwent preoperative RT (median dose, 50 Gy) and 54% underwent postoperative RT (median dose, 60 Gy). Also, 28% received doxorubicin-based chemotherapy as a part of their treatment. Results: The median follow-up was 9.1 years. The overall survival rate at 5 and 10 years was 87% and 79%, respectively. The corresponding disease-free survival rates were 81% and 73%. The local control rate at $5 years was 97%. The actuarial rate of distant metastases at 5 and 10 years was 15% and 24%, respectively. Of the 27 patients who developed distant metastases, 48% did so in the retroperitoneum, 22% in other extrapulmonary soft tissues, 22% in the lung, 15% in bone, and 4% in the liver. Conclusion: The results of our study have shown that RT and conservation surgery for localized myxoid liposarcoma provide excellent local control. Distant metastatic relapse tended to occur in the retroperitoneum and other nonpulmonary soft tissues. Therefore, staging and surveillance imaging should include the abdomen and pelvis, as well as the thorax, for patients with localized myxoid liposarcoma. Ó 2008 Elsevier Inc. Myxoid liposarcoma, Local control, Radiotherapy, Conservation surgery.
INTRODUCTION Liposarcoma is the second most common soft-tissue sarcoma, and approximately one-half of these tumors are further classified as myxoid liposarcoma (1). Myxoid liposarcoma occurs most commonly in the extremities (1, 2) and exhibits distinctive genetic and clinical characteristics. Cytogenetically, almost all myxoid liposarcomas have a specific reciprocal translocation of chromosomes 12 and 16, t(12;16) (q13;p11), resulting in an oncogenic hybrid protein, TLS/ FUS-CHOP (3–6). Although the presence of this molecular genetic abnormality has not been shown to have prognostic significance (7), it does provide a method for confirmation of the diagnosis of myxoid liposarcoma. Several investigations have reported patterns of failure in myxoid liposarcoma that differ from those observed in other soft-tissue sarcomas (8–12). Although most soft-tissue sarco-
mas metastasize to the lung, myxoid liposarcoma has shown a propensity to metastasize to nonpulmonary sites and less frequently to the lungs than other soft-tissue sarcomas. Furthermore, evidence has shown that, among the soft-tissue sarcomas, myxoid liposarcoma is particularly radiosensitive (2, 13). Studies of this tumor have shown tumor regression (13) or high local control rates (2) superior to the local treatment responses seen for other soft-tissue sarcomas. No studies have been reported in which all patients were treated with both radiotherapy (RT) and conservation surgery for myxoid liposarcoma. Therefore, we performed a retrospective analysis of all patients with nonmetastatic myxoid liposarcoma treated with conservation surgery and RT at The University of Texas M.D. Anderson Cancer Center (MDACC) between 1960 and 2003. Our goals were to analyze the local control rates and patterns of failure in a large single-institution series.
Reprint requests to: B. Ashleigh Guadagnolo, M.D., M.P.H, Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 97, Houston, TX 77030. Tel: (713) 563-2300; Fax: (713) 563-2331; E-mail:
[email protected] Conflict of interest: none. Received April 5, 2007, and in revised form July 2, 2007. Accepted for publication July 4, 2007. 760
Myxoid liposarcoma treated with conservation surgery and RT d B. A. GUADAGNOLO et al.
PATIENTS AND METHODS The patients were identified through a search of the Department of Radiation Oncology database at the MDACC. Between 1960 and 2003, 207 consecutive patients with nonmetastatic liposarcoma were treated with conservation surgery and RT at the MDACC. Of these 207 patients, 127 had myxoid liposarcoma and constituted the study population. The review of the data for this investigation began after approval from our institution’s investigation review board. Each patient had undergone a full history, complete physical examination, routine blood tests, and chest radiography. Computed tomography and magnetic resonance imaging were also performed according to availability during the years encompassed by this analysis. Patients with distant metastases at presentation to the MDACC were excluded from this review. The histologic diagnosis of myxoid liposarcoma was confirmed in each case by a review of the slides by a pathologist at the MDACC. The grading of myxoid liposarcoma remains controversial. The Association of Directors of Anatomic and Surgical Pathology has suggested that grading of individual cases of myxoid liposarcoma could be prognostically useful (14), and a report by Kilpatrick et al. (15) found that an increasing proportion of round cell differentiation conferred an increasing metastatic propensity. However, accurate quantification of the round cell fraction requires whole specimen study. At the MDACC, in lieu of such an examination, we have recognized a ‘‘cellular myxoid’’ variant (16) with a somewhat greater metastatic potential, but have not otherwise graded individual cases of myxoid liposarcoma, regarding this histologic type as intermediate grade by definition.
Patient and tumor characteristics Of the 127 patients, 55 (43%) were female, and 72 (57%) were male. The mean and median patient age was 41 and 39 years (range, 14–79 years), respectively. The distribution of lesions by anatomic site was as follows. Three (2%) were located in the head-and-neck region: one in the orbit, one on the face, and one in the neck. Two (2%) were located in the deep trunk, both in the retroperitoneum. Thirteen (10%) were located in the superficial trunk: seven in the buttocks, two on the back, two on the flank, one in the axilla, and one in the thoracic paraspinal area. Four (3%) occurred in an upper extremity: three in an upper arm and one in a hand. The remaining 105 (83%) occurred in a lower extremity: 6 in the groin, 70 in a thigh, 12 in a knee, 13 in a leg, and 4 in an ankle. Thus, 109 lesions (86%) arose in an extremity, and only 18 (14%) occurred in a trunk or head-and-neck location. The tumor size was documented in 125 patients and ranged from 1.5 to 35 cm in the maximal dimension. The mean and median size was 11.8 and 10 cm, respectively. The tumor stage according to the American Joint Committee on Cancer staging criteria (17) was Stage T1 (#5 cm) for 17 (13%) and Stage T2 (>5 cm) for 108 (85%).
Treatment The basic treatment strategy for soft-tissue sarcomas at the MDACC has been a combination of conservation surgical excision and RT (18–20). Before 1979, at the MDACC, all definitive surgery was undertaken before RT. After 1979, the preferred approach to management was preoperative RT followed by surgery, unless the patient presented to the MDACC having undergone adequate surgery at an outside institution. The goal of surgical excision was to obtain tumor-free margins of 1–3 cm (21). When this margin size was not feasible because of the proximity of the tumor to adjacent critical structures, an attempt was made to obtain tumor-free margins with as much margin as possible. Because the MDACC is a referral center, most patients had undergone at least a biopsy of their tumor,
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and 74 (58%) had had their tumors grossly excised before referral. On the basis of the physical examination findings, review of the operative report, review of the pathology report, and communication with the referring surgeon, 35 patients were determined to have adequate margins and no additional surgery was performed. Four patients without gross disease but with positive margins were determined to be ineligible for additional conservation surgery and thus proceeded to RT. These 39 patients were classified as undergoing treatment with surgery and postoperative RT. Twenty-three patients who had presented to the MDACC having undergone inadequate wide local excision, an excisional biopsy, or an incisional biopsy underwent additional surgery followed by RT. Six patients presented to the MDACC who had not undergone previous surgery and were treated with surgery followed by RT. Thus, 68 patients (54%) were classified as having undergone surgery followed by postoperative RT . The remaining 59 patients (46%) had undergone preoperative RT followed by conservation surgery. A significantly larger proportion of patients treated with preoperative RT plus surgery had a tumor size >5 cm (93%) compared with those treated with surgery and postoperative RT (80%; p = 0.04). In 122 patients, RT consisted of external beam RT alone. One patient received external beam RT and intraoperative RT, and 4 patients received brachytherapy alone. External beam RT was administered with megavoltage ($60Co energy) beams. For preoperative RT, the irradiation target volume was the tumor plus a 5–7-cm margin to a dose of approximately 50 Gy (median, 50; range, 46–60 Gy). For postoperative RT, the standard approach was to treat the surgical bed plus a 5–7-cm margin to a dose of 50 Gy, followed by a field size reduction to boost the dose to the surgical bed another 10–15 Gy. The goal was to treat postoperatively to a dose of approximately 60 Gy (median, 62 Gy; range, 50–71.5 Gy). The median fraction size for patients treated pre- and postoperatively was 2.0 Gy (range, 1.13–2.5 Gy). It has not been our practice at the MDACC to irradiate entire muscle compartments from origin to insertion unless tumor coverage necessitated it. Efforts were made to avoid treating the entire circumference of an extremity or long bone and to spare joints when possible without compromising tumor coverage. Since 1980, chemotherapy has been increasingly used for softtissue sarcomas at our institution. Of the 127 patients, 35 (28%) received chemotherapy as a part of their treatment. All chemotherapy was doxorubicin based, and the other agents used included cyclophosphamide, vincristine, dacarbazine, or ifosfamide, according to the combinations deemed appropriate at the various periods encompassed by this study. The use of chemotherapy was left to the discretion of the patient’s medical oncologist. In view of the general classification of myxoid liposarcoma as an intermediate-grade malignancy, the threshold for the use of chemotherapy was typically a tumor size of >10 cm. Thus, only 11 (17%) of 66 patients with tumors <10 cm underwent adjuvant chemotherapy compared with 24 (41%) of 59 with tumors $10 cm. Finally, 11 patients (9%) received some chemotherapy concurrently with RT.
Follow-up and statistical analysis The median follow-up of patients alive at last contact was 9.1 years (range, 2.7–33 years). The actuarial curves for survival, disease-specific survival, local control, distant metastatic relapse, disease-free survival, and complications were calculated using the Kaplan-Meier method (22), and the log–rank statistic was used to test for significance. Multivariate regression analysis was performed using the Cox proportional hazards model (23). The covariates evaluated were gender, tumor size, tumor site, treatment sequence (surgery plus postoperative RT vs. preoperative RT plus surgery), use of chemotherapy (yes vs. no), and margin status (positive/unknown vs.
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and 71% at 5, 10, and 15 years, respectively. The last relapse occurred at 10.9 years.
Fig. 1. Observed overall survival for all 127 patients. Vertical bars represent 95% confidence intervals. negative). The chi-square statistic was used to test for the significance of differences between proportions, and the nonparametric Mann-Whitney U test (24) was used to test for the significance of differences between mean values.
RESULTS Survival The actuarial overall survival for these patients is shown in Fig. 1. The overall survival rate at 5, 10, and 15 years was 87%, 79%, and 71%, respectively. The disease-specific survival (DSS) rate was 89%, 83%, and 78% at 5, 10, and 15 years, respectively. The last death from disease occurred at 15.6 years. The disease-free survival rate was 81%, 73%,
Patterns of failure Of the 127 patients, 31 (24%) developed disease relapse. Of these, 4 patients (3%) experienced local relapse, and for all 4, local relapse was the site of first relapse. The actuarial local control rate was 97% at 5 years, and no local relapses were observed after 3.6 years. The interval to the development of local relapse from completion of RT was 6–43 months (median, 14 months). No patients developed regional nodal metastases. Of the 127 patients, 27 (21%) developed distant metastases (DMs), and all patients who developed DMs did so as the site of first relapse. The interval to the development of DM was 0.8 months to 10.9 years (median, 27 months) after RT completion, and 85% of DMs had occurred by 5 years. The median survival time after the first relapse was 88 months. The DSS rate after the first relapse was 29% and 22% at 5 and 10 years, respectively. Only 1 patient with isolated local recurrence died of disease, with a corresponding 10-year DSS rate of 75% for patients with an isolated local recurrence. Conversely, patients with metastatic relapse had a DSS rate of 23% and 15% at 5 and 10 years, respectively. Local recurrence Of the four local recurrences, three occurred in the irradiation field and one at the edge of the treatment field. Table 1 summarizes the local control rates with respect to the tumor and treatment characteristics. Because of the few events observed, meaningful statistical analyses could not be performed. Local control in all subgroups appeared excellent.
Table 1. Univariate analysis of local control rates Characteristic Entire cohort Size (cm) #5 >5 #10 >10 Site Head and neck Superficial trunk Deep trunk Upper limb Lower limb Treatment sequence Surgery then RT RT then surgery Margin status Positive Unknown Negative Radiation dose* (Gy) #56 >56
n (%) 127
Actuarial 5-y LC rate (%) 97
17 (15) 108 (85) 66 (57) 59 (43)
100 96 97 96
3 (2) 2 (2) 13 (10) 4 (3) 105 (83)
67 100 50 75 99
68 (54) 59 (46)
94 100
11 (9) 25 (20) 91 (72)
100 87 99
62 (50) 61 (50)
98 95
Abbreviations: LC = local control; RT = radiotherapy. * Including patients who underwent external beam RT.
Distant metastases The actuarial DM-free rate at 5 and 10 years was 85% and 76%, respectively. One additional patient developed DM at 10.9 years. Of the 27 patients with DMs, the site of metastatic
Fig. 2. Freedom from distant metastases according to tumor size. Note, abscissa starts at 60%.
Myxoid liposarcoma treated with conservation surgery and RT d B. A. GUADAGNOLO et al.
Table 2. Summary of radiotherapy-related complications Interval to treatment Age at Tumor Radiation completion (mo) treatment (y) site dose (Gy) 50 66 60 39
Knee Leg Thigh Thigh
70.0 66.71 64.5 60.0
5 61 72 3
52
Thigh
50.0
7
43 30 41
Thigh Thigh Thigh
60.0 50.0 60.4
4 3 19
36 43
Thigh Ankle
50.0 64.0
11 28
36
Thigh
60.0
18
Complication type (severity*) Edema (mild) Edema (severe) Fracture (severe) Radiation necrosis with fracture of femur (severe) Edema (moderate) Edema (mild) Edema (mild) Cellulitis (severe) Fibrosis (mild) Stress fracture of distal tibia (moderate) Fibrosis (severe)
* Mild, required no treatment; moderate, required medical intervention; severe, required surgery or hospitalization.
relapse was the retroperitoneum in 13 (48%), extrapulmonary soft tissue in 6 (22%), lung in 6 (22%), bone in 4 (15%), and liver in 1 (4%). Univariate analysis did not reveal any of the following factors to be significantly prognostic for DM: tumor size, tumor site, margin status, treatment sequence, or the use of adjuvant chemotherapy. Similarly, none of these factors significantly influenced the development of DM on multivariate analysis of these characteristics. The DM-free survival rates according to tumor size are shown in Fig. 2. Complications Eleven patients (9%) experienced RT-related complications. The actuarial complication rate at 5 and 10 years was
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7% and 10%, respectively. The interval to the development of complications was 3–72 months (median, 11 months; mean, 21 months). The RT-related complications are summarized in Table 2. Univariate and multivariate analyses of the tumor- and treatment-related variables, including radiation dose, showed that no factors significantly influenced the development of RT-related complications. DISCUSSION Our analysis revealed an excellent local control rate of 97% at 10 years for patients with myxoid liposarcoma treated with conservation surgery and RT. Furthermore, of 11 patients who had positive margins after conservation surgery, none experienced local disease relapse, suggesting that RT is effective in controlling this tumor. We also demonstrated that, in contrast to other soft-tissue sarcomas, pulmonary metastases were not the most common site of distant failure in our series, but rather that most metastases involved the retroperitoneum, abdomen, and extrapulmonary soft tissue. These findings are supported by those of reports from other investigators and have implications regarding the treatment and surveillance of patients with localized myxoid liposarcoma. Our series is the only one reported in which all patients received both RT and conservation surgery as primary therapy for localized myxoid liposarcoma. Our analysis showed superior local control outcomes compared with other series in which patients were treated with heterogeneous treatment approaches. Spillane and associates (8) reported an 84% 5-year local control rate for their series of 50 patients treated with surgery alone, RT alone, or a combination of surgery and RT. Another report by ten Heuvel et al. (25) showed a 67% crude local control rate in their series of 49 patients that included patients treated with surgery alone or surgery followed by RT. In that study, the investigators also analyzed 42 patients who underwent marginal resection or excision with positive margins. Of these 42 patients, 24 received postoperative RT, resulting in a 92% local control rate compared with a 56% local control rate for the 18 patients who did not
Fig. 3. (a) Staging computed tomography scan of abdomen from June 2002 for patient with primary myxoid liposarcoma of right calf. No evidence of metastases found in this study. He received 50 Gy preoperatively followed by resection of primary tumor, and completed local therapy in December 2002. (b) Surveillance computed tomography scan performed in December 2004 revealed large intra-abdominal metastases arising from retroperitoneal soft tissue. This patient did not experience local tumor recurrence.
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receive RT. This difference in local control rates for patients with a marginal or positive-margin excision was significant (p = 0.01), supporting the assertion that myxoid liposarcoma is a particularly radioresponsive histopathologic finding. The radiation responsiveness of myxoid liposarcoma was specifically addressed in volumetric studies performed by investigators at the Princess Margaret Hospital. Pitson et al. (13) performed an analysis of the pre- and post-treatment tumor volumes for patients treated with 50 Gy of preoperative RT for patients with either myxoid liposarcoma or malignant fibrous histiocytoma. In their case-control analysis, they found a significant reduction in the mean tumor volume in patients with myxoid liposarcoma, with significantly greater absolute and proportional volumetric reductions than those seen for malignant fibrous histiocytoma, the most common histologic subtype of soft-tissue sarcomas. Another distinctive feature that sets myxoid liposarcoma apart from other soft-tissue sarcomas is its tendency toward nonpulmonary metastases. Spillane and associates (8) reported that, in their series, the most common sites of metastases were to the retroperitoneum, abdominal wall, and abdominal cavity. These data are similar to our findings regarding the pattern of soft-tissue metastases. Figure 3 shows abdominal computed tomography scans from 1 patient who was treated with RT and surgery for localized disease in the right calf and was subsequently found to have a large abdominal metastasis arising from the retroperitoneum 2 years after completing treatment. Investigators at the Memorial Sloan-Kettering Cancer Center have also analyzed patterns of metastases for their experience of patients with myxoid liposarcoma and found distinctive patterns of distant relapse. Schwab et al. (12) reported that 17% of patients developed skeletal metastases and that skeletal metastases represented more than one-half of metastatic events in their series of 230 patients. They also noted that many of these skeletal metastases occurred early on for patients who developed metastatic relapse, usually before the development of lung metastases. Although our retrospective review was not the optimal study design to offer firm therapeutic recommendations regarding management, our local control rates do suggest that
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conservation surgery and RT offer appropriate local treatment for nonmetastatic myxoid liposarcoma. Also, our review did not show that chemotherapy affected survival or the development of DMs; however, this study design and the study population’s treatment characteristics with respect to chemotherapy were not appropriate for meaningful conclusions regarding systemic therapy for this disease. Moreover, myxoid liposarcoma is an intermediate grade malignancy and has demonstrated metastatic potential, as seen by our distant metastatic rate of 24% at 10 years. Patel and colleagues (26) reported significant objective response rates for doxorubicinand dacarbazine-based chemotherapy. This is pertinent for this malignancy, because patients tend to present with large, bulky tumors, and chemotherapy offers a means to reduce the primary tumor size and facilitate local therapy. CONCLUSION Our findings have clinical implications for the treatment and surveillance of patients with localized myxoid liposarcoma. It is our clinical practice to treat patients with localized myxoid liposarcoma with conservation surgery and RT. For patients presenting with a tumor size >10 cm, consideration is given to treatment intensification with neoadjuvant doxorubicin-based chemotherapy. For local therapy, we recommend 50 Gy in 25 fractions of preoperative RT followed by surgery. The goal of surgical excision is to obtain a 1–3-cm tumor-free margin. In cases in which postoperative RT is warranted, we recommend 60 Gy (64–68 Gy for positive margins) using a shrinking field technique, with a conedown to the smaller field after 50 Gy. In myxoid liposarcoma, it appears reasonable to expect adequate local control after RT, even in the setting of positive margins. This might aid clinical decision-making in difficult cases in which wide tumor-free margins or re-excision might not be possible owing to the proximity of tumor to critical normal structures. Finally, the distinctive pattern of metastatic relapse seen in myxoid liposarcoma necessitates that staging and surveillance imaging include the abdomen and pelvis, as well as the thorax, because extrapulmonary soft-tissue metastases are common sites for DMs.
REFERENCES 1. Weiss SW, Goldblum JR. Liposarcoma. In: Weiss SW, Goldblum JR, Enzinger FM, editors. Enzinger and Weiss’s soft tissue tumors. 4th ed. St. Louis: Mosby; 2001. p. 641– 693. 2. Zagars GK, Goswitz MS, Pollack A. Liposarcoma: Outcome and prognostic factors following conservation surgery and radiation therapy. Int J Radiat Oncol Biol Phys 1996;36: 311–319. 3. Antonescu CR, Elahi A, Humphrey M, et al. Specificity of TLSCHOP rearrangement for classic myxoid/round cell liposarcoma: Absence in predominantly myxoid well-differentiated liposarcomas. J Mol Diagn 2000;2:132–138. 4. Crozat A, Aman P, Mandahl N, et al. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 1993;363:640–644.
5. Knight JC, Renwick PJ, Cin PD, et al. Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: Molecular and cytogenetic analysis. Cancer Res 1995;55:24–27. 6. Sreekantaiah C, Karakousis CP, Leong SP, et al. Cytogenetic findings in liposarcoma correlate with histopathologic subtypes. Cancer 1992;69:2484–2495. 7. Antonescu CR, Tschernyavsky SJ, Decuseara R, et al. Prognostic impact of p53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: A molecular and clinicopathologic study of 82 cases. Clin Cancer Res 2001;7: 3977–3987. 8. Spillane AJ, Fisher C, Thomas JM. Myxoid liposarcoma—The frequency and the natural history of nonpulmonary soft tissue metastases. Ann Surg Oncol 1999;6:389–394.
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9. Estourgie SH, Nielsen GP, Ott MJ. Metastatic patterns of extremity myxoid liposarcoma and their outcome. J Surg Oncol 2002;80:89–93. 10. Pearlstone DB, Pisters PW, Bold RJ, et al. Patterns of recurrence in extremity liposarcoma: Implications for staging and follow-up. Cancer 1999;85:85–92. 11. Behranwala KA, Roy P, Giblin V, et al. Intra-abdominal metastases from soft tissue sarcoma. J Surg Oncol 2004;87:116–120. 12. Schwab JH, Boland P, Guo T, et al. Skeletal metastases in myxoid liposarcoma: An unusual pattern of distant spread. Ann Surg Oncol 2007;14:1507–1514. 13. Pitson G, Robinson P, Wilke D, et al. Radiation response: An additional unique signature of myxoid liposarcoma. Int J Radiat Oncol Biol Phys 2004;60:522–526. 14. Association of Directors of Anatomic and Surgical Pathology. Recommendations for the reporting of soft tissue sarcomas. Hum Pathol 1999;30:3–7. 15. Kilpatrick SE, Doyon J, Choong PF, et al. The clinicopathologic spectrum of myxoid and round cell liposarcoma: A study of 95 cases. Cancer 1996;77:1450–1458. 16. Evans HL. Liposarcoma: A study of 55 cases with a reassessment of its classification. Am J Surg Pathol 1979;3:507–523. 17. Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging handbook. 6th ed. New York: Springer; 2002.
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18. Lindberg RD, Martin RG, Romsdahl MM, et al. Conservative surgery and postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 1981;47:2391–2397. 19. Barkley HT Jr., Martin RG, Romsdahl MM, et al. Treatment of soft tissue sarcomas by preoperative irradiation and conservative surgical resection. Int J Radiat Oncol Biol Phys 1988;14: 693–699. 20. Ballo MT, Zagars GK. Radiation therapy for soft tissue sarcoma. Surg Oncol Clin North Am 2003;12:449–467. vii. 21. Tanabe KK, Pollock RE, Ellis LM, et al. Influence of surgical margins on outcome in patients with preoperatively irradiated extremity soft tissue sarcomas. Cancer 1994;73:1652–1659. 22. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 23. Cox D. Regression models and life tables. J R Stat Soc B 1972; 34:187–220. 24. Altman DG. Practical statistics for medical research. London: Chapman and Hall; 1991. 25. ten Heuvel SE, Hoekstra HJ, van Ginkel RJ, et al. Clinicopathologic prognostic factors in myxoid liposarcoma: A retrospective study of 49 patients with long-term follow-up. Ann Surg Oncol 2007;14:222–229. 26. Patel SR, Burgess MA, Plager C, et al. Myxoid liposarcoma: Experience with chemotherapy. Cancer 1994;74:1265–1269.
doi:10.1016/j.ijrobp.2007.07.2337
CLINICAL INVESTIGATION
Sarcoma
EXCELLENT LOCAL CONTROL RATES AND DISTINCTIVE PATTERNS OF FAILURE IN MYXOID LIPOSARCOMA TREATED WITH CONSERVATION SURGERY AND RADIOTHERAPY B. ASHLEIGH GUADAGNOLO, M.D., M.P.H.,* GUNAR K. ZAGARS, M.D.,* MATTHEW T. BALLO, M.D.,* SHREYASKUMAR R. PATEL, M.D.,y VALERAE O. LEWIS, M.D.,z ROBERT S. BENJAMIN, M.D.,y x AND RAPHAEL E. POLLOCK, M.D., PH.D. Departments of *Radiation Oncology, y Sarcoma Medical Oncology, z Orthopaedic Oncology, and x Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Purpose: To evaluate the local control rates and patterns of metastatic relapse in patients with localized myxoid liposarcoma treated with conservation surgery and radiotherapy (RT). Patients and Methods: Between 1960 and 2003, 127 patients with non-metastatic myxoid liposarcoma were treated with conservation surgery and RT at our institution. The median patient age was 39 years (range, 14–79 years). Of the 127 patients, 46% underwent preoperative RT (median dose, 50 Gy) and 54% underwent postoperative RT (median dose, 60 Gy). Also, 28% received doxorubicin-based chemotherapy as a part of their treatment. Results: The median follow-up was 9.1 years. The overall survival rate at 5 and 10 years was 87% and 79%, respectively. The corresponding disease-free survival rates were 81% and 73%. The local control rate at $5 years was 97%. The actuarial rate of distant metastases at 5 and 10 years was 15% and 24%, respectively. Of the 27 patients who developed distant metastases, 48% did so in the retroperitoneum, 22% in other extrapulmonary soft tissues, 22% in the lung, 15% in bone, and 4% in the liver. Conclusion: The results of our study have shown that RT and conservation surgery for localized myxoid liposarcoma provide excellent local control. Distant metastatic relapse tended to occur in the retroperitoneum and other nonpulmonary soft tissues. Therefore, staging and surveillance imaging should include the abdomen and pelvis, as well as the thorax, for patients with localized myxoid liposarcoma. Ó 2008 Elsevier Inc. Myxoid liposarcoma, Local control, Radiotherapy, Conservation surgery.
INTRODUCTION Liposarcoma is the second most common soft-tissue sarcoma, and approximately one-half of these tumors are further classified as myxoid liposarcoma (1). Myxoid liposarcoma occurs most commonly in the extremities (1, 2) and exhibits distinctive genetic and clinical characteristics. Cytogenetically, almost all myxoid liposarcomas have a specific reciprocal translocation of chromosomes 12 and 16, t(12;16) (q13;p11), resulting in an oncogenic hybrid protein, TLS/ FUS-CHOP (3–6). Although the presence of this molecular genetic abnormality has not been shown to have prognostic significance (7), it does provide a method for confirmation of the diagnosis of myxoid liposarcoma. Several investigations have reported patterns of failure in myxoid liposarcoma that differ from those observed in other soft-tissue sarcomas (8–12). Although most soft-tissue sarco-
mas metastasize to the lung, myxoid liposarcoma has shown a propensity to metastasize to nonpulmonary sites and less frequently to the lungs than other soft-tissue sarcomas. Furthermore, evidence has shown that, among the soft-tissue sarcomas, myxoid liposarcoma is particularly radiosensitive (2, 13). Studies of this tumor have shown tumor regression (13) or high local control rates (2) superior to the local treatment responses seen for other soft-tissue sarcomas. No studies have been reported in which all patients were treated with both radiotherapy (RT) and conservation surgery for myxoid liposarcoma. Therefore, we performed a retrospective analysis of all patients with nonmetastatic myxoid liposarcoma treated with conservation surgery and RT at The University of Texas M.D. Anderson Cancer Center (MDACC) between 1960 and 2003. Our goals were to analyze the local control rates and patterns of failure in a large single-institution series.
Reprint requests to: B. Ashleigh Guadagnolo, M.D., M.P.H, Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 97, Houston, TX 77030. Tel: (713) 563-2300; Fax: (713) 563-2331; E-mail:
[email protected] Conflict of interest: none. Received April 5, 2007, and in revised form July 2, 2007. Accepted for publication July 4, 2007. 760
Myxoid liposarcoma treated with conservation surgery and RT d B. A. GUADAGNOLO et al.
PATIENTS AND METHODS The patients were identified through a search of the Department of Radiation Oncology database at the MDACC. Between 1960 and 2003, 207 consecutive patients with nonmetastatic liposarcoma were treated with conservation surgery and RT at the MDACC. Of these 207 patients, 127 had myxoid liposarcoma and constituted the study population. The review of the data for this investigation began after approval from our institution’s investigation review board. Each patient had undergone a full history, complete physical examination, routine blood tests, and chest radiography. Computed tomography and magnetic resonance imaging were also performed according to availability during the years encompassed by this analysis. Patients with distant metastases at presentation to the MDACC were excluded from this review. The histologic diagnosis of myxoid liposarcoma was confirmed in each case by a review of the slides by a pathologist at the MDACC. The grading of myxoid liposarcoma remains controversial. The Association of Directors of Anatomic and Surgical Pathology has suggested that grading of individual cases of myxoid liposarcoma could be prognostically useful (14), and a report by Kilpatrick et al. (15) found that an increasing proportion of round cell differentiation conferred an increasing metastatic propensity. However, accurate quantification of the round cell fraction requires whole specimen study. At the MDACC, in lieu of such an examination, we have recognized a ‘‘cellular myxoid’’ variant (16) with a somewhat greater metastatic potential, but have not otherwise graded individual cases of myxoid liposarcoma, regarding this histologic type as intermediate grade by definition.
Patient and tumor characteristics Of the 127 patients, 55 (43%) were female, and 72 (57%) were male. The mean and median patient age was 41 and 39 years (range, 14–79 years), respectively. The distribution of lesions by anatomic site was as follows. Three (2%) were located in the head-and-neck region: one in the orbit, one on the face, and one in the neck. Two (2%) were located in the deep trunk, both in the retroperitoneum. Thirteen (10%) were located in the superficial trunk: seven in the buttocks, two on the back, two on the flank, one in the axilla, and one in the thoracic paraspinal area. Four (3%) occurred in an upper extremity: three in an upper arm and one in a hand. The remaining 105 (83%) occurred in a lower extremity: 6 in the groin, 70 in a thigh, 12 in a knee, 13 in a leg, and 4 in an ankle. Thus, 109 lesions (86%) arose in an extremity, and only 18 (14%) occurred in a trunk or head-and-neck location. The tumor size was documented in 125 patients and ranged from 1.5 to 35 cm in the maximal dimension. The mean and median size was 11.8 and 10 cm, respectively. The tumor stage according to the American Joint Committee on Cancer staging criteria (17) was Stage T1 (#5 cm) for 17 (13%) and Stage T2 (>5 cm) for 108 (85%).
Treatment The basic treatment strategy for soft-tissue sarcomas at the MDACC has been a combination of conservation surgical excision and RT (18–20). Before 1979, at the MDACC, all definitive surgery was undertaken before RT. After 1979, the preferred approach to management was preoperative RT followed by surgery, unless the patient presented to the MDACC having undergone adequate surgery at an outside institution. The goal of surgical excision was to obtain tumor-free margins of 1–3 cm (21). When this margin size was not feasible because of the proximity of the tumor to adjacent critical structures, an attempt was made to obtain tumor-free margins with as much margin as possible. Because the MDACC is a referral center, most patients had undergone at least a biopsy of their tumor,
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and 74 (58%) had had their tumors grossly excised before referral. On the basis of the physical examination findings, review of the operative report, review of the pathology report, and communication with the referring surgeon, 35 patients were determined to have adequate margins and no additional surgery was performed. Four patients without gross disease but with positive margins were determined to be ineligible for additional conservation surgery and thus proceeded to RT. These 39 patients were classified as undergoing treatment with surgery and postoperative RT. Twenty-three patients who had presented to the MDACC having undergone inadequate wide local excision, an excisional biopsy, or an incisional biopsy underwent additional surgery followed by RT. Six patients presented to the MDACC who had not undergone previous surgery and were treated with surgery followed by RT. Thus, 68 patients (54%) were classified as having undergone surgery followed by postoperative RT . The remaining 59 patients (46%) had undergone preoperative RT followed by conservation surgery. A significantly larger proportion of patients treated with preoperative RT plus surgery had a tumor size >5 cm (93%) compared with those treated with surgery and postoperative RT (80%; p = 0.04). In 122 patients, RT consisted of external beam RT alone. One patient received external beam RT and intraoperative RT, and 4 patients received brachytherapy alone. External beam RT was administered with megavoltage ($60Co energy) beams. For preoperative RT, the irradiation target volume was the tumor plus a 5–7-cm margin to a dose of approximately 50 Gy (median, 50; range, 46–60 Gy). For postoperative RT, the standard approach was to treat the surgical bed plus a 5–7-cm margin to a dose of 50 Gy, followed by a field size reduction to boost the dose to the surgical bed another 10–15 Gy. The goal was to treat postoperatively to a dose of approximately 60 Gy (median, 62 Gy; range, 50–71.5 Gy). The median fraction size for patients treated pre- and postoperatively was 2.0 Gy (range, 1.13–2.5 Gy). It has not been our practice at the MDACC to irradiate entire muscle compartments from origin to insertion unless tumor coverage necessitated it. Efforts were made to avoid treating the entire circumference of an extremity or long bone and to spare joints when possible without compromising tumor coverage. Since 1980, chemotherapy has been increasingly used for softtissue sarcomas at our institution. Of the 127 patients, 35 (28%) received chemotherapy as a part of their treatment. All chemotherapy was doxorubicin based, and the other agents used included cyclophosphamide, vincristine, dacarbazine, or ifosfamide, according to the combinations deemed appropriate at the various periods encompassed by this study. The use of chemotherapy was left to the discretion of the patient’s medical oncologist. In view of the general classification of myxoid liposarcoma as an intermediate-grade malignancy, the threshold for the use of chemotherapy was typically a tumor size of >10 cm. Thus, only 11 (17%) of 66 patients with tumors <10 cm underwent adjuvant chemotherapy compared with 24 (41%) of 59 with tumors $10 cm. Finally, 11 patients (9%) received some chemotherapy concurrently with RT.
Follow-up and statistical analysis The median follow-up of patients alive at last contact was 9.1 years (range, 2.7–33 years). The actuarial curves for survival, disease-specific survival, local control, distant metastatic relapse, disease-free survival, and complications were calculated using the Kaplan-Meier method (22), and the log–rank statistic was used to test for significance. Multivariate regression analysis was performed using the Cox proportional hazards model (23). The covariates evaluated were gender, tumor size, tumor site, treatment sequence (surgery plus postoperative RT vs. preoperative RT plus surgery), use of chemotherapy (yes vs. no), and margin status (positive/unknown vs.
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and 71% at 5, 10, and 15 years, respectively. The last relapse occurred at 10.9 years.
Fig. 1. Observed overall survival for all 127 patients. Vertical bars represent 95% confidence intervals. negative). The chi-square statistic was used to test for the significance of differences between proportions, and the nonparametric Mann-Whitney U test (24) was used to test for the significance of differences between mean values.
RESULTS Survival The actuarial overall survival for these patients is shown in Fig. 1. The overall survival rate at 5, 10, and 15 years was 87%, 79%, and 71%, respectively. The disease-specific survival (DSS) rate was 89%, 83%, and 78% at 5, 10, and 15 years, respectively. The last death from disease occurred at 15.6 years. The disease-free survival rate was 81%, 73%,
Patterns of failure Of the 127 patients, 31 (24%) developed disease relapse. Of these, 4 patients (3%) experienced local relapse, and for all 4, local relapse was the site of first relapse. The actuarial local control rate was 97% at 5 years, and no local relapses were observed after 3.6 years. The interval to the development of local relapse from completion of RT was 6–43 months (median, 14 months). No patients developed regional nodal metastases. Of the 127 patients, 27 (21%) developed distant metastases (DMs), and all patients who developed DMs did so as the site of first relapse. The interval to the development of DM was 0.8 months to 10.9 years (median, 27 months) after RT completion, and 85% of DMs had occurred by 5 years. The median survival time after the first relapse was 88 months. The DSS rate after the first relapse was 29% and 22% at 5 and 10 years, respectively. Only 1 patient with isolated local recurrence died of disease, with a corresponding 10-year DSS rate of 75% for patients with an isolated local recurrence. Conversely, patients with metastatic relapse had a DSS rate of 23% and 15% at 5 and 10 years, respectively. Local recurrence Of the four local recurrences, three occurred in the irradiation field and one at the edge of the treatment field. Table 1 summarizes the local control rates with respect to the tumor and treatment characteristics. Because of the few events observed, meaningful statistical analyses could not be performed. Local control in all subgroups appeared excellent.
Table 1. Univariate analysis of local control rates Characteristic Entire cohort Size (cm) #5 >5 #10 >10 Site Head and neck Superficial trunk Deep trunk Upper limb Lower limb Treatment sequence Surgery then RT RT then surgery Margin status Positive Unknown Negative Radiation dose* (Gy) #56 >56
n (%) 127
Actuarial 5-y LC rate (%) 97
17 (15) 108 (85) 66 (57) 59 (43)
100 96 97 96
3 (2) 2 (2) 13 (10) 4 (3) 105 (83)
67 100 50 75 99
68 (54) 59 (46)
94 100
11 (9) 25 (20) 91 (72)
100 87 99
62 (50) 61 (50)
98 95
Abbreviations: LC = local control; RT = radiotherapy. * Including patients who underwent external beam RT.
Distant metastases The actuarial DM-free rate at 5 and 10 years was 85% and 76%, respectively. One additional patient developed DM at 10.9 years. Of the 27 patients with DMs, the site of metastatic
Fig. 2. Freedom from distant metastases according to tumor size. Note, abscissa starts at 60%.
Myxoid liposarcoma treated with conservation surgery and RT d B. A. GUADAGNOLO et al.
Table 2. Summary of radiotherapy-related complications Interval to treatment Age at Tumor Radiation completion (mo) treatment (y) site dose (Gy) 50 66 60 39
Knee Leg Thigh Thigh
70.0 66.71 64.5 60.0
5 61 72 3
52
Thigh
50.0
7
43 30 41
Thigh Thigh Thigh
60.0 50.0 60.4
4 3 19
36 43
Thigh Ankle
50.0 64.0
11 28
36
Thigh
60.0
18
Complication type (severity*) Edema (mild) Edema (severe) Fracture (severe) Radiation necrosis with fracture of femur (severe) Edema (moderate) Edema (mild) Edema (mild) Cellulitis (severe) Fibrosis (mild) Stress fracture of distal tibia (moderate) Fibrosis (severe)
* Mild, required no treatment; moderate, required medical intervention; severe, required surgery or hospitalization.
relapse was the retroperitoneum in 13 (48%), extrapulmonary soft tissue in 6 (22%), lung in 6 (22%), bone in 4 (15%), and liver in 1 (4%). Univariate analysis did not reveal any of the following factors to be significantly prognostic for DM: tumor size, tumor site, margin status, treatment sequence, or the use of adjuvant chemotherapy. Similarly, none of these factors significantly influenced the development of DM on multivariate analysis of these characteristics. The DM-free survival rates according to tumor size are shown in Fig. 2. Complications Eleven patients (9%) experienced RT-related complications. The actuarial complication rate at 5 and 10 years was
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7% and 10%, respectively. The interval to the development of complications was 3–72 months (median, 11 months; mean, 21 months). The RT-related complications are summarized in Table 2. Univariate and multivariate analyses of the tumor- and treatment-related variables, including radiation dose, showed that no factors significantly influenced the development of RT-related complications. DISCUSSION Our analysis revealed an excellent local control rate of 97% at 10 years for patients with myxoid liposarcoma treated with conservation surgery and RT. Furthermore, of 11 patients who had positive margins after conservation surgery, none experienced local disease relapse, suggesting that RT is effective in controlling this tumor. We also demonstrated that, in contrast to other soft-tissue sarcomas, pulmonary metastases were not the most common site of distant failure in our series, but rather that most metastases involved the retroperitoneum, abdomen, and extrapulmonary soft tissue. These findings are supported by those of reports from other investigators and have implications regarding the treatment and surveillance of patients with localized myxoid liposarcoma. Our series is the only one reported in which all patients received both RT and conservation surgery as primary therapy for localized myxoid liposarcoma. Our analysis showed superior local control outcomes compared with other series in which patients were treated with heterogeneous treatment approaches. Spillane and associates (8) reported an 84% 5-year local control rate for their series of 50 patients treated with surgery alone, RT alone, or a combination of surgery and RT. Another report by ten Heuvel et al. (25) showed a 67% crude local control rate in their series of 49 patients that included patients treated with surgery alone or surgery followed by RT. In that study, the investigators also analyzed 42 patients who underwent marginal resection or excision with positive margins. Of these 42 patients, 24 received postoperative RT, resulting in a 92% local control rate compared with a 56% local control rate for the 18 patients who did not
Fig. 3. (a) Staging computed tomography scan of abdomen from June 2002 for patient with primary myxoid liposarcoma of right calf. No evidence of metastases found in this study. He received 50 Gy preoperatively followed by resection of primary tumor, and completed local therapy in December 2002. (b) Surveillance computed tomography scan performed in December 2004 revealed large intra-abdominal metastases arising from retroperitoneal soft tissue. This patient did not experience local tumor recurrence.
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receive RT. This difference in local control rates for patients with a marginal or positive-margin excision was significant (p = 0.01), supporting the assertion that myxoid liposarcoma is a particularly radioresponsive histopathologic finding. The radiation responsiveness of myxoid liposarcoma was specifically addressed in volumetric studies performed by investigators at the Princess Margaret Hospital. Pitson et al. (13) performed an analysis of the pre- and post-treatment tumor volumes for patients treated with 50 Gy of preoperative RT for patients with either myxoid liposarcoma or malignant fibrous histiocytoma. In their case-control analysis, they found a significant reduction in the mean tumor volume in patients with myxoid liposarcoma, with significantly greater absolute and proportional volumetric reductions than those seen for malignant fibrous histiocytoma, the most common histologic subtype of soft-tissue sarcomas. Another distinctive feature that sets myxoid liposarcoma apart from other soft-tissue sarcomas is its tendency toward nonpulmonary metastases. Spillane and associates (8) reported that, in their series, the most common sites of metastases were to the retroperitoneum, abdominal wall, and abdominal cavity. These data are similar to our findings regarding the pattern of soft-tissue metastases. Figure 3 shows abdominal computed tomography scans from 1 patient who was treated with RT and surgery for localized disease in the right calf and was subsequently found to have a large abdominal metastasis arising from the retroperitoneum 2 years after completing treatment. Investigators at the Memorial Sloan-Kettering Cancer Center have also analyzed patterns of metastases for their experience of patients with myxoid liposarcoma and found distinctive patterns of distant relapse. Schwab et al. (12) reported that 17% of patients developed skeletal metastases and that skeletal metastases represented more than one-half of metastatic events in their series of 230 patients. They also noted that many of these skeletal metastases occurred early on for patients who developed metastatic relapse, usually before the development of lung metastases. Although our retrospective review was not the optimal study design to offer firm therapeutic recommendations regarding management, our local control rates do suggest that
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conservation surgery and RT offer appropriate local treatment for nonmetastatic myxoid liposarcoma. Also, our review did not show that chemotherapy affected survival or the development of DMs; however, this study design and the study population’s treatment characteristics with respect to chemotherapy were not appropriate for meaningful conclusions regarding systemic therapy for this disease. Moreover, myxoid liposarcoma is an intermediate grade malignancy and has demonstrated metastatic potential, as seen by our distant metastatic rate of 24% at 10 years. Patel and colleagues (26) reported significant objective response rates for doxorubicinand dacarbazine-based chemotherapy. This is pertinent for this malignancy, because patients tend to present with large, bulky tumors, and chemotherapy offers a means to reduce the primary tumor size and facilitate local therapy. CONCLUSION Our findings have clinical implications for the treatment and surveillance of patients with localized myxoid liposarcoma. It is our clinical practice to treat patients with localized myxoid liposarcoma with conservation surgery and RT. For patients presenting with a tumor size >10 cm, consideration is given to treatment intensification with neoadjuvant doxorubicin-based chemotherapy. For local therapy, we recommend 50 Gy in 25 fractions of preoperative RT followed by surgery. The goal of surgical excision is to obtain a 1–3-cm tumor-free margin. In cases in which postoperative RT is warranted, we recommend 60 Gy (64–68 Gy for positive margins) using a shrinking field technique, with a conedown to the smaller field after 50 Gy. In myxoid liposarcoma, it appears reasonable to expect adequate local control after RT, even in the setting of positive margins. This might aid clinical decision-making in difficult cases in which wide tumor-free margins or re-excision might not be possible owing to the proximity of tumor to critical normal structures. Finally, the distinctive pattern of metastatic relapse seen in myxoid liposarcoma necessitates that staging and surveillance imaging include the abdomen and pelvis, as well as the thorax, because extrapulmonary soft-tissue metastases are common sites for DMs.
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