Long-Term Results Following Postoperative Radiotherapy for Soft Tissue Sarcomas of the Extremity

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation: Sarcoma

Long-Term Results Following Postoperative Radiotherapy for Soft Tissue Sarcomas of the Extremity Lisa McGee, MD,* Daniel J. Indelicato, MD,*,x Roi Dagan, MD,* Christopher G. Morris, MS,* Jacquelyn A. Knapik, MD,y John D. Reith, MD,y Mark T. Scarborough, MD,z C. Parker Gibbs, MD,z Robert B. Marcus, Jr, MD,*,x and Robert A. Zlotecki, MD, PhD* From the Departments of *Radiation Oncology, yPathology, and zOrthopedics, University of Florida College of Medicine, Gainesville, Florida; and xUniversity of Florida Proton Therapy Institute, Jacksonville, Florida Received Aug 1, 2011, and in revised form Jan 23, 2012. Accepted for publication Jan 25, 2012

Summary We retrospectively reviewed long-term outcomes of 173 patients treated with postoperative radiotherapy for localized extremity soft tissue sarcoma (STS) and identified variables affecting the therapeutic ratio. This large single-institution series confirms that postoperative radiotherapy for STS of the extremities provides good long-term disease control with acceptable toxicity. Our experience supports recurrent presentation and older age as adverse prognostic factors for local control.

Purpose: To review long-term outcomes following postoperative radiotherapy (RT) for extremity soft tissue sarcoma (STS) and identify variables affecting the therapeutic ratio. Methods and Materials: Between 1970 and 2008, 173 patients with localized extremity STS were treated with postoperative radiation. No patients received prior irradiation. Sixteen percent of tumors had recurred after initial surgery alone; 89% of tumors were high grade. The median patient age was 57 years (range, 18-86 years). Sixty-one percent underwent >1 surgery before RT in an attempt to achieve wide negative margins. Final margin status was negative in 70% and marginal or microscopically positive in 30%. The median time between final surgery and start of RT was 40 days. The median RT dose was 65 Gy (range, 49-74 Gy). The median follow-up for all patients was 10.4 years and 13.2 years among survivors. Results: At 10 years, local control (LC), cause-specific survival (CSS), and overall survival (OS) rates were 87%, 80%, and 70%, respectively, with 89% of local failures occurring within 3 years after treatment. On multivariate analysis, age >55 years (82% vs 93%, P<.05) and recurrent presentation (67% vs 91%, P<.05) were associated with inferior 10-year LC. The LC according to final margin status was 90% for wide negative margins vs 79% for marginal/microscopically positive margins (PZ.08). Age >55 years and local recurrence were associated with inferior CSS and OS on multivariate analysis. Twelve percent of patients experienced grade 3þ toxicity; 12 of these occurred in patients with tumors of the proximal lower extremity, with the most common toxicity of pathologic fracture occurring in 6.3%. Conclusions: This large single-institution series confirms that postoperative RT for STS of the extremities provides good long-term disease control with acceptable toxicity. Our experience supports recurrent presentation and older age as adverse prognostic factors for LC. Ó 2012 Elsevier Inc. Keywords: Postoperative radiotherapy, Soft tissue sarcoma, Outcomes

Reprint requests to: Daniel J. Indelicato, MD, University of Florida Proton Therapy Institute, 2015 North Jefferson St, Jacksonville, FL 32206.

Int J Radiation Oncol Biol Phys, Vol. 84, No. 4, pp. 1003e1009, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.01.074

Tel: (904) 588-1800; Fax: (904) 588-1300; E-mail: dindelicato@ floridaproton.org Conflict of interest: none.

1004 McGee et al.

International Journal of Radiation Oncology  Biology  Physics

Introduction

detailed quantitative information regarding the size of their tumor in either the pathology report or preoperative diagnostic imaging reports. All patients were staged according to the Musculoskeletal Tumor Society (MSTS) (4) staging system as well as the American Joint Committee on Cancer (AJCC) Staging Manual, 7th edition (5). The MSTS stage distribution was as follows: stage IA, 8 patients; stage IB, 10 patients; stage IIA, 87 patients; and stage IIIB, 68 patients (Table 2). When staged according to the AJCC guidelines (5), the distribution was as follows: stage IA, 8 patients; stage IB, 5 patients; stage IIA, 72 patients; stage IIB, 1 patient; and 40 patients were unknown. Toxicities were recorded for each patient and scored according to National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0 (6). Specific attention was paid to wound-healing complications, in-field fractures, vascular complications, and second malignancies.

Soft tissue sarcomas (STSs) are a rare group of malignant tumors that arise from mesenchymal cells and can occur in any part of the body, most commonly in the extremity and trunk. The standard treatment includes surgical excision plus radiotherapy (RT), both of which may impair near- and long-term limb function. Multiple studies have proven that wide local excision plus adjuvant RT either in the pre- or postoperative setting offer similar local control (LC) and survival compared with amputation or radical excision (1, 2). For high-risk patients, local excision without adjuvant RT is associated with an increased likelihood of recurrence (2, 3). Because of the rarity and heterogeneity of STS, there are few prospective randomized trials evaluating different methods of treatment, and most have a limited duration of follow-up. Therefore, we rely heavily on retrospective outcome studies to form considerations of therapeutic ratio and subsequent treatment recommendations. This series reviews long-term results of patients with STS of the extremities treated with surgery and postoperative RT at the University of Florida.

Methods and Materials Patients The medical records of 1028 patients with a diagnosis of STS who were treated with RT at the University of Florida were reviewed in accordance with the University of Florida Institutional Review Board Protocol 70-2003 and the Health Insurance Portability and Accountability Act. Of these patients, 173 were found to have localized STS of the extremity treated with postoperative external-beam RT. Patients were excluded for the following reasons: 43 had metastatic disease at presentation, 212 had sarcomas located in a nonextremity site, 334 were treated with preoperative RT, 213 had a histology not consistent with malignant sarcoma, 19 were treated with definitive RT alone, and 25 were excluded for other reasons, such as receiving RT at another institution, prior RT to the site, synchronous primaries, postoperative RT consisting of brachytherapy alone, or pediatric presentation. The 173 patients included herein were curatively treated with postoperative RT at the University of Florida between 1970 and 2008. All patients had biopsy-proven histologic confirmation of STS. The majority (51%) of the sarcomas were malignant fibrous histiocytoma (MFH) in histology, with liposarcoma being the next most common subtype (18%). Sixty-six percent of tumors were located in the lower extremity, most of which were located in the proximal lower limb (52%). Sixteen percent of tumors were recurrent after initial management with surgery alone. Of all tumors, 89% were high grade. The median age was 57 years (range, 18-86 years). The local extent of disease was evaluated by plain X-ray, computed tomography (CT), and/or magnetic resonance imaging (MRI) depending on the treatment era and histologic subtype. Workup for distant disease included either a chest X-ray, chest CT, and/or positron emission tomography (PET/CT) depending on the treatment era. In many cases in which the initial surgery was performed at an outside hospital, preoperative volumetric imaging of the tumor was unavailable. Therefore, 40 patients lacked

Treatment All patients were initially treated with surgery; 76% of first operations were performed at an outside hospital, and 24% were performed at our institution. Regarding the number of operations performed, 39% of patients had only 1, whereas 57% had a second reexcision performed, and 7% required 3 or more operations before RT. These numbers reflect the general institutional policy to recommend reexcision of the tumor bed to confirm a negative margin if the initial surgery was considered to be a nononcologic resection. Final margins were negative in 70% of patients and marginal or microscopically positive in 30%. If patients had gross residual disease, they were excluded from this study. All patients received postoperative RT. In patients who present to the University of Florida with high-risk (ie, large, infiltrative, and/or high-grade), unresected STS, our preference is preoperative RT. However, most patients in this study were not candidates for preoperative RT because they already had either a partial or complete excision when they were referred to our center. For patients who have had initial incomplete surgery at an outside institution, it is our general institutional policy to reexcise the tumor and then treat with postoperative RT. General indications for postoperative RT included high grade, marginal or microscopically positive margins, and large tumors located deep to the fascia. The techniques of radiotherapy evolved with technology over time; however, the following principles were applied: patients had the involved extremity immobilized for simulation and daily during treatment by custom-made molds. The target radially included the entire involved compartment, surgical bed, and drain sites and was expanded longitudinally by approximately 5-7 cm as defined by physical examination and imaging. A reduction was performed after delivery of 45-50 Gy. In patients for whom preoperative imaging was not available, the target volumes were created using postoperative imaging of the tumor bed and surgical clips, if available. Target volumes were initially defined by fluoroscopic simulation and later by CT simulation when it became available in our department in 1993. When available, MRI fusion was used to enhance target delineation. Treatment goals included delivering a homogenous dose to the target volume; sparing 2-3 cm of uninvolved soft tissue, half the diameter of long bones, and uninvolved neurovascular or osseous structures; avoiding the extensor surface of the knees and lower legs; and ensuring an

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Postoperative RT for STS of the extremity 1005

entire joint space was not included in our RT fields. Patient setup was verified initially with conventional portal imaging. Electronic portal imaging was used when it became available in our department in 2002. In our series, the mean RT dose was 65 Gy (range, 49-74 Gy) typically delivered through an initial phase of 45-50 Gy followed by a boost to a smaller volume. The median dose for patients with negative, marginal, and microscopically positive margins was 62.9 Gy (3.6 Gy), 63.8 Gy (5.3 Gy) and, 64 Gy (6.4 Gy), respectively. Of all patients, 47% were treated with twice-daily fractionation, and 53% were treated with once-daily fractionation. The median interval between surgery and RT was 40 days. Seven patients (4%) received adjuvant chemotherapy, most commonly an Adriamycin-based regimen (n Z 4).

Follow-up and observed outcomes Follow-up care included a medical history and physical examination at progressive intervals beyond treatment. Follow-up imaging of the primary site was individualized based on baseline risk, symptoms, and treatment era. Depending on the treatment era, a chest X-ray or CT of the chest to evaluate lung metastases was performed at least annually for the first 5 years.

Outcome measurement and statistics The observed outcomes were LC, overall survival (OS), causespecific survival (CSS), and toxicity. CSS was defined by death from recurrent or progressive disease. For our analysis, the initiation of RT was considered the start date. All statistical computations were accomplished with SAS and JMP software (SAS Institute, Cary, NC). The Kaplan-Meier product-limit method provided estimates of LC, CSS, and OS. Univariate and multivariate analyses were performed to assess the significance of specific factors influencing the above outcomes.

Results Follow-up At the time of analysis, the median follow-up for all patients was 10.4 years (range, 0.3-32.1 years). The median follow-up for living patients was 13.2 years (range, 1.7-32.1 years).

Local control LC was achieved in 153 patients. Actuarial LC rates for all patients were 89% and 87% at 5 and 10 years, respectively (Fig). The median time to a local failure was 1.4 years (range, 0.4-6.7 years). Of the 20 local recurrences, 17 occurred within the first 3 years. On univariate analysis, age greater than 55 years (93% vs 82% at 10 years) and recurrent presentation (91% vs 67% at 10 years) were associated with inferior LC (PZ.04 and PZ.0013, respectively). Other variables evaluated and found not to affect LC included the following: stage (MSTS and AJCC), initial surgery location, RT fractionation scheme, treatment era (1970-1993 vs 1994-2008), and margin status (Table 1). The LC according to final margin status was 90% for wide negative margins vs 79% for marginal/microscopically positive margins (PZ.08). Reliable

Fig. Ten-year local control rates for all patients. CSS Z cause-specific survival; DMFS Z distant metastasis-free survival; LC Z local control; LC þ AFS Z local control and amputationfree survival; OS Z overall survival. subgroup statistical analyses could not be performed on the marginal vs microscopically positive margins because of an insufficient numbers of events. There was a trend toward increased local recurrence in patients who required reexcision of the tumor bed compared with those who only needed a single operation (92% vs 80%, PZ.09). Recurrent presentation maintained a statistically significant association with LC on multivariate analysis (Table 2). An exploratory subset analysis evaluating LC of margin status by RT dose did not demonstrate a clear benefit to increasing the dose above 66 Gy for patients with microscopically positive or marginal margins. Of the 49 patients with marginal or positive margins, 6 patients were treated to <60 Gy with 100% LC, 33 patients were treated to 60-66 Gy with 78% LC, and 10 patients were treated to >66 Gy with 88% LC (PZ.36).

Distant metastasis Actuarial distant metastasis-free survival rates at 5 and 10 years were 82% and 81%, respectively. The most common site of metastasis was the lung (27 of 32 patients or 84% of all metastases). The median time to metastasis was 1.3 years (range, 0.2-8.5 years). Of the 27 patients who developed metastatic pulmonary disease, 11 underwent no salvage attempt; 7 were treated with surgery alone; 1 received chemotherapy alone; 1 was treated with surgery and RT; 3 were treated with surgery plus chemotherapy; 1 was treated with surgery, RT, and chemotherapy; and 1 patient was palliated with low-dose radiation alone. Details of metastatic management were unavailable for 2 patients. Of the 14 patients who underwent a known salvage attempt, 2 demonstrated longterm disease control (14%). Both patients were treated with a wedge resection of a solitary pulmonary metastasis, with 1 patient surviving 17 years and the other surviving >23 years (still alive at last follow-up).

Survival Actuarial OS rates at 5 and 10 years were 79% and 70%, respectively. On univariate and multivariate analysis (Tables 3 and 4), the factors that were statistically associated with

International Journal of Radiation Oncology  Biology  Physics

1006 McGee et al. Table 1

Univariate analysis Local control Variable

Age 55 y >55 y Gender Female Male Presentation Primary Recurrent MSTS stage IA (n Z 8) or IB (n Z 10) IIA (n Z 87) or IIB (n Z 68) AJCC stage 1A (n Z 8) or 1B (n Z 5) 2A (n Z 72) or 2B (n Z 1) III Unknown Tumor diameter (cm) 5 cm >5-10 cm >10 cm Unknown Final surgical margins Negative (wide) Marginal/close Positive (intralesional) Unknown (þ contaminated) No. of operations 1 2 3 Location of initial surgery Outside hospital Shands-University of Florida RT fractionation Once daily Twice daily Treatment era 1965-1993 1994-2009

Cause-specific survival

Overall survival

n

5y

10 y

P value

5y

10 y

P value

5y

10 y

P value

77 96

93% 85%

93% 82%

.0467

93% 77%

90% 72%

.0014

92% 69%

85% 59%

<.0001

79 94

89% 89%

89% 85%

.5584

93% 77%

90% 72%

.0061

87% 73%

80% 62%

.0095

145 28

92% 73%

91% 67%

.0013

85% 81%

82% 73%

.2432

79% 79%

71% 67%

.3114

18 155

75% 91%

75% 89%

.1343

94% 83%

87% 80%

.3809

89% 78%

75% 70%

.3488

13 73 47 40

73% 87% 98% NA

73% 87% 91% NA

.1984

92% 85% 80% NA

81% 83% 74% NA

.6384

85% 81% 74% NA

66% 75% 62% NA

.1465

83 33 13 44

87% 90% 100% NA

87% 86% 89% NA

.8787

86% 81% 92% NA

84% 73% 82% NA

.5504

81% 75% 84% NA

75% 55% 75% NA

.0795

118 36 13 6

91% 80% 91% NA

90% 75% 91% NA

.0851

87% 71% 100% NA

84% 61% 100% NA

.0060

80% 71% 92% NA

71% 61% 82% NA

.7706

67 99 7

84% 91% 100%

80% 91% 100%

.0977

80% 86% 100%

74% 84% 100%

.1051

75% 81% 86%

65% 73% 86%

.0550

131 42

89% 90%

89% 83%

.5630

85% 82%

83% 72%

.1802

79% 79%

72% 64%

.0691

82 91

84% 93%

82% 91%

.0831

80% 89%

75% 85%

.0518

74% 84%

65% 75%

.0429

94 79

85% 93%

84% 91%

.1574

82% 87%

79% 81%

.5606

78% 81%

70% 69%

.9924

NA

NA

NA

NA

NA

NA

NA

NA

NA

Abbreviations: AJCC Z American Joint Committee on Cancer; MSTS Z Musculoskeletal Tumor Society; NA Z not applicable; RT Z radiotherapy.

improved overall survival were female gender (80% vs 62% at 10 years), age 55 years (85% vs 59% at 10 years), and LC (75% vs 40% at 10 years). Actuarial CSS at 5 and 10 years was 84% and 80%, respectively. On univariate and multivariate analyses (Tables 3 and 4), the only factor that was found to affect CSS was age 55 years (90% vs 72% at 10 years; PZ.0014). Actuarial amputation-free survival rates at 5 and 10 years were 95% and 91%, respectively. Actuarial LC plus amputation-free survival rates at 5 and 10 years were 87% and 85%, respectively.

Toxicity Twenty-one patients (12%) experienced a late adverse event of grade 3 or higher according to the National Cancer Institute

Common Terminology Criteria for Adverse Events, version 4.0 (6). Half of these toxicities (6.3%) were because of fractures of irradiated bone (12 fractures in 11 patients; Table 3). Three of these patients had periosteal stripping at the time of surgery. Fractures were all located in the lower extremity and were more likely to occur in females (70%). Three patients had stress fractures that healed without surgical repair; 4 patients had initial orthopedic procedures performed and then healed without incident. An additional 4 patients had initial orthopedic repair of their fractures and required additional therapy; 3 of these 4 patients required additional orthopedic procedures to correct nonunion and eventually healed, and 1 patient required amputation for nonunion of fracture. Other toxicity included delayed wound healing in 6 patients (3.4%), vascular complications in 2 patients (1.1%), and second malignancy in 1 patient (0.5%). There were 4 patients who

Volume 84  Number 4  2012 Table 2

Postoperative RT for STS of the extremity 1007

Multivariate analysis Local control added as a prognostic value

Variable

Local control P value

Overall survival P value

Cause-specific survival P value

Overall survival P value

Cause-specific survival P value

Age Gender Intent MSTS stage Margins Prior operations Fractionation Dose Local control

.1466 .7861 .0026 .1603 .1138 .9996 .1432 .5743 e

<.0001 .0348 .5845 .8072 .9382 .2994 .0583 .9311 e

.0048 .1042 .4462 .5757 .0464 .9996 .0511 .6139 e

<.0001 .0448 .6379 .8382 .8619 .4979 .0725 .7901 .0173

.032 .0292 .9201 .5008 .4394 .8229 .1928 .5609 <.0001

Abbreviation: MSTS Z Musculoskeletal Tumor Society.

required an amputation secondary to complications, including 2 wound events, 1 vascular event, and 1 for treatment of a radiationinduced osteosarcoma. The following variables were evaluated by univariate and multivariate analysis to assess impact on toxicity: age, tumor site, RT fractionation, gender, number of surgeries, and treatment era. No specific variables were found to have a statistically significant association with a subsequent complication (Table 4). There were no acute grade 3 toxicities during treatment.

Discussion STS comprises <1% of new cancer diagnoses every year in the United States. Jemal et al (7) estimated 10,660 new cases to have occured in 2009 and approximately 3820 patients to die from this disease in this same time period. Our series demonstrates a longterm survival of 70% in patients with extremity sarcoma who undergo postoperative RT. This is similar to overall survival results reported in other series with long-term follow-up of 70%-79% (3, 8). Distant metastasis-free survival in our series was 81%, which is similar to the rate reported by Yang et al of 75%. CSS in this series was 84%. Among our long-term survivors, the likelihood of amputation for a tumor recurrence and/or treatment complication was <10%. These long-term data further validate the role of postoperative RT as part of limb conservation in selected high-risk patients with STS of the extremity. Adequate surgical excision is fundamental to the LC of STS of the extremity. Wide local excision plus adjuvant RT in either the preoperative or postoperative setting offers comparable LC and survival to amputation or radical excision (1, 2). In tumors with high-risk features, adjuvant RT improves LC (3, 9). In studies powered by enough patients with long-term follow-up, improved LC may translate into improved OS, particularly in patients with large (>5 cm) high-grade tumors (10, 11). The relationship

Table 3

Toxicity

Toxicity Wound Fracture Vascular Radiation dermatitis Second malignancy

No. of Patients (%) 6 11 3 2 1

(3.4%) (6.3%) (1.7%) (1.1%) (0.5%)

observed between LC and OS in our cohort adds support to this notion. Pre- and postoperative RT achieve similar rates of LC (8, 9). At the University of Florida, most patients are treated with preoperative RT if they present before STS excision, and LC is excellent at 93% (12). Preoperative RT allows for the use of a smaller RT field size and lower doses but may be associated with increased wound complications in patients with tumors of the lower extremity (9). Furthermore, preoperative RT may not always be an option when an excisional biopsy of an unknown soft tissue mass is carried out for diagnosis. Our data suggest that with the proper approach to patient selection and treatment, the therapeutic ratio is not dramatically different with postoperative RT than preoperative RT. In this series of 173 patients with localized STS of the extremity treated with postoperative RT, the 10-year LC rate was 87%. These results are similar to other rates of LC reported in the Table 4

Toxicity by variable

Variable

No. of patients who experienced toxicity (%)

Age 55 y >55 y Site Upper proximal Upper distal Lower proximal Lower distal Fractionation Once daily Twice daily Gender Female Male No. of prior operations 1 2 3 Treatment era 1970-1993 1994-2008 Note: No P values were significant.

8 (10.3) 13 (13.5) 3 2 12 4

(8.1) (9) (13.3) (16.6)

10 (12.1) 11 (12) 13 (16.4) 8 (8.5) 6 (8.9) 14 (14.1) 1 (14.2) 13 (13.8) 8 (10.1)

1008 McGee et al.

International Journal of Radiation Oncology  Biology  Physics

literature ranging from 80%-100% (Table 5) (3, 8, 9, 13). It is well documented that variables such as high grade, large tumor size, increasing age, deep location, recurrent presentation, microscopic positive margins, and gross tumor remaining after surgical excision may have a negative impact on LC (1, 14). However, in this series, which excluded patients with gross residual disease and routinely used an escalated boost dose for patients with microscopically positive margins, only recurrent presentation significantly affected LC. Our data indicate that with long-term follow-up, 89% of local failures occur within the first 3 years after RT. On this basis, in the absence of symptoms or abnormalities on physical examination, detailed volumetric imaging of the extremity may not be justified beyond 3 years. In a similar retrospective analysis by Whooley et al, 28 of 29 local recurrences were diagnosed on the basis of an abnormal physical examination (15). Current National Comprehensive Cancer Network guidelines recommend medical history and physical examination with a chest X-ray every 3-6 months for the first 2-3 years, every 6 months in years 4 and 5, and annually thereafter. Routine imaging of the primary site is not recommended (15), and our series provides data to support these guidelines. When achievable, microscopically negative margin status is associated with superior LC (16-18). However, the definition of an adequate margin distance is variable: a series from the University of Helsinki study demonstrates that surgical margins >2.5 cm from the tumor are associated with improved LC in patients undergoing combined-modality local therapy. When combined with adjuvant RT, margins of at least 1 cm, 2 cm, and 2.5 cm yielded LC rates of 83.3%, 85.9%, and 89.2%, respectively. Surgical margin status was found to have an independent prognostic value for LC (16). Another series demonstrates that margins >2 mm have improved LC on univariate analysis (17). In this

current series, we did not find margin status to significantly affect LC, but patients with close or positive margins routinely received a higher total radiation dose. This practice is supported by evidence from The University of Texas MD Anderson Cancer Center (Houston, TX) where doses 64 Gy independently correlated with improved LC (19). We did not observe a clear benefit to increasing the dose above 66 Gy in patients with microscopically positive margins. However, because there were only 11 patients evaluated in this subgroup, our ability to draw any conclusion is limited. Comprehensive complication rates are inconsistently recorded in the literature for postoperative RT for STS, with most reports focusing primarily on wound complication rates (8, 9, 13). The overall complication rate in our series was 12% for any grade 3 or higher toxicity, with most toxicities being fractures and wound complications. In particular, 6 patients (3.4%) had grade 3 or higher wound complication rates, 2 of whom ultimately required amputation. This is slightly lower compared with other woundcomplication rates reported in the literature of 6%-17% following postoperative RT for STS (8, 9, 13). Eleven patients (6.3%) had a total of 12 fractures; a finding that is similar to the Princess Margaret Hospital (Toronto, ON) series in which 4.4% of patients treated with either preoperative or postoperative RT had fractures (20). Our study has its limitations. The observational nature of our findings prohibits direct causal interpretation. There is also an inherent selection bias in all retrospective studies, but with a relatively rare disease like STS, randomized data are scarce. All of our patients were treated at a single institution under uniform policies; however, our experience spans 4 decades during which imaging, chemotherapy, surgical technique, and RT methods have changed. Regardless of tumor type, all attempts to analyze longterm outcomes data are subject to the biases of treatment evolution

Table 5

Literature review

Author, institution, publication year Cheng et al (18), 1996, University of Minnesota

No. of patients Median Wound Inclusion criteria Total Postop RT follow-up complications Nonmetastatic extremity STS

112

64

5.3 y

8%

Grade 2-3 STS, retroperitoneal excluded Yang et al (9), 1998, National Nonmetastatic Cancer Institute extremity STS

453

165

8.1 y

6%

141

70y

9.6 y

e

O’Sullivan et al (15), 2002, National Cancer Institute of Canada McGee et al (Present series), University of Florida

Nonmetastatic extremity STS

190

96

3.3 y

17%

Nonmetastatic extremity STS

e

173

10.4 y

5%

Pollack et al (14), 1998, MD Anderson Cancer Center

Abbreviations: Postop Z postoperative; RT Z radiotherapy; STS Z soft tissue sarcoma. * high-grade only. y Forty-four postoperative RT patients were high grade.

Outcomes for patients who received postop RT Recurrence-free survival, 5 y: 67%  12% Overall survival, 5 y: 79%  11% Local control, 5 y: 91%  8% Local control, 10 y: 88%

Distant metastasis-free survival, 10 y: 75%* Overall survival, 10 y: 75%* Local control, 10 y: 100%* Local control: 90% Progression-free survival: 60% Overall survival: 70% Distant metastasis-free survival, 10 y: 81% Overall survival, 10 y: 70% Local control, 10 y: 87%

Volume 84  Number 4  2012 and stage migration. Despite these shortcomings, this study represents one of the largest single-institution series reporting comprehensive long-term outcomes following postoperative RT for STS of the extremity.

Conclusions Postoperative RT for STS of the extremity provides good longterm disease control with acceptable toxicity. Our experience supports the conclusion that recurrent presentation and older age are adverse prognostic factors for LC following multimodality local therapy.

References 1. 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. 2. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of softtissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982; 196:305-315. 3. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197-203. 4. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980; 106-120. 5. American Joint Committee on Cancer. AJCC Cancer Staging Handbook. 7th ed. New York, NY: Springer; 2010. 6. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v4.0, DCTD, NCI, NIH, DHHS. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/ctcae_index.pdf#searchZ“common terminology”. Updated April 15, 2010. Accessed June 4, 2010. 7. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225-249.

Postoperative RT for STS of the extremity 1009 8. Pollack A, Zagars GK, Goswitz MS, et al. Preoperative vs postoperative radiotherapy in the treatment of soft tissue sarcomas: a matter of presentation. Int J Radiat Oncol Biol Phys 1998;42: 563-572. 9. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235-2241. 10. Koshy M, Rich SE, Mohiuddin MM. Improved survival with radiation therapy in high-grade soft tissue sarcomas of the extremities: a SEER analysis. Int J Radiat Oncol Biol Phys 2010;77:203-209. 11. Gronchi A, Lo VS, Colombo C, et al. Extremity soft tissue sarcoma in a series of patients treated at a single institution: local control directly impacts survival. Ann Surg 2010;251:506-511. 12. Dagan R, McGee L, Morris CG, et al. Is marginal excision relevant after preoperative radiation therapy for soft tissue sarcoma of the extremity [abstract]? Int J Rad Oncol Bio Phys 2011;78:S86. 13. Cheng EY, Dusenbery KE, Winters MR, et al. Soft tissue sarcomas: preoperative versus postoperative radiotherapy. J Surg Oncol 1996;61: 90-99. 14. Vraa S, Keller J, Nielsen OS, et al. Prognostic factors in soft tissue sarcomas: the Aarhus experience. Eur J Cancer 1998;34:1876-1882. 15. Whooley BP, Gibbs JF, Mooney MM, et al. Primary extremity sarcoma: what is the appropriate follow-up? Ann Surg Oncol 2000;7: 9-14. 16. Sampo M, Tarkkanen M, Huuhtanen R, et al. Impact of the smallest surgical margin on local control in soft tissue sarcoma. Br J Surg 2008;95:237-243. 17. Novais EN, Demiralp B, Alderete J, et al. Do surgical margin and local recurrence influence survival in soft tissue sarcomas? Clin Orthop Relat Res 2010;468:3003-3011. 18. Jebsen NL, Trovik CS, Bauer HC, et al. Radiotherapy to improve local control regardless of surgical margin and malignancy grade in extremity and trunk wall soft tissue sarcoma: a Scandinavian sarcoma group study. Int J Radiat Oncol Biol Phys 2008;71:1196-1203. 19. Zagars GK, Ballo MT. Significance of dose in postoperative radiotherapy for soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2003;56: 473-481. 20. Dickie CI, Parent AL, Griffin AM, et al. Bone fractures following external beam radiotherapy and limb-preservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume, tumor location and dose. Int J Radiat Oncol Biol Phys 2009; 75:1119-1124.