Multidisciplinary Approach to Treatment of Soft Tissue Sarcomas Requiring Complex Oncologic Resections

Accepted Manuscript Multidisciplinary Approach to Treatment of Soft Tissue Sarcomas Requiring Complex Oncologic Resections Nadia Awad, Richard Lackman, Katherine McMackin, Tae Won Kim, Joseph Lombardi, Francis Caputo PII:

S0890-5096(18)30485-0

DOI:

10.1016/j.avsg.2018.04.035

Reference:

AVSG 3920

To appear in:

Annals of Vascular Surgery

Received Date: 4 June 2017 Revised Date:

14 April 2018

Accepted Date: 19 April 2018

Please cite this article as: Awad N, Lackman R, McMackin K, Kim TW, Lombardi J, Caputo F, Multidisciplinary Approach to Treatment of Soft Tissue Sarcomas Requiring Complex Oncologic Resections, Annals of Vascular Surgery (2018), doi: 10.1016/j.avsg.2018.04.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1 1

Title Page Multidisciplinary Approach to Treatment of Soft Tissue Sarcomas Requiring Complex

3

Oncologic Resections

4

RI PT

2

5

Nadia Awad1, Richard Lackman2, Katherine McMackin1, Tae Won Kim2,

6

Joseph Lombardi1, Francis Caputo1

8

Division of Vascular Surgery, Department of Surgery

SC

1

7

Cooper Medical School of Rowan University, Camden, NJ 2

Department of Orthopedic Surgery

M AN U

9 10

Cooper Medical School of Rowan University, Camden, NJ

11 12

TE D

13 Corresponding Author Present Address:

15

Nadia Awad

16

5401 Old York Road

17

Suite 203

18

Philadelphia, PA 19141

19

E-mail: [email protected]

20

Phone: (215) 456-6178

21

Fax: (215) 456-6204

AC C

EP

14

ACCEPTED MANUSCRIPT 2 22

Abstract

23

Objective: To review the experience and outcome of utilizing a multidisciplinary team, including

25

vascular surgery and orthopedic surgery, in the operative treatment of soft tissue sarcomas (STS)

26

at an academic, tertiary care hospital.

RI PT

24

27 Methods:

SC

28

A retrospective review was performed of all patients who underwent elective STS

30

resection between July 1, 2012 and January 31, 2015, since the addition of a specialized cancer

31

treatment center and a dedicated oncologic division of orthopedic surgery. Surgical cases

32

performed in conjunction with both orthopedic and vascular surgery were reviewed.

M AN U

29

33 Results:

TE D

34

Sixty-three patients underwent sixty-six surgical resections for STS during the study

36

period. There were no perioperative deaths. Fifty-two lower extremity resections (78.8%), six

37

upper extremity resections (9.1%), and eight pelvic resections (12.1%) were performed. Sixteen

38

cases required a vascular intervention (24.2%). These interventions included bypass in two

39

patients (12.5%), primary repair of a named vessel in four patients (25%), and ligation of a

40

named vessel in ten patients (62.5%). Three patients had local recurrence of their tumor (4.5%),

41

requiring further resection during the follow-up period. Seven patients required a primary

42

amputation (10.6%). The average size of tumor removed was 1,776 mL, ranging from 5 mL to

43

36,300 mL.

44

AC C

EP

35

ACCEPTED MANUSCRIPT 3 45

Conclusion: The quality of surgical resection is paramount in optimal treatment of STS, however,

47

wide resection of STS can result in prolonged operative times, significant blood loss, vascular

48

complications, and functional deficits. A multidisciplinary surgical team including orthopedic

49

and vascular teams may improve treatment by optimizing complex resections that may require

50

involved vascular control or reconstruction.

AC C

EP

TE D

M AN U

SC

RI PT

46

ACCEPTED MANUSCRIPT 4 51

Manuscript

52

Introduction Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of adult tumors

54

and are treated primarily with wide surgical resection and local radiation. STS represent a

55

heterogeneous group of tumors with multiple histologic subtypes. Each subtype of STS exhibits

56

different clinical and cellular behaviors, resulting in differing responses to both local and

57

systemic therapies.1,2 While these tumors may occur anywhere in the body, including the

58

retroperitoneum and pelvis, STS occur most often in the extremities. Metastasis is most

59

commonly found in the lungs and up to 10% of patients present with metastatic disease.3,4

M AN U

SC

RI PT

53

The most important factor in predicting local recurrence is positive margins on surgical

61

excision1-4, therefore adequate resection margins are necessary to achieve optimal local

62

treatment. STS often occur adjacent to, or are primarily involved with neurovascular structures

63

and thus pose the challenge of achieving negative margins while preserving function. Since the

64

inception of adjuvant and neo-adjuvant radiation, reports have shown promising rates of limb

65

salvage while also achieving adequate resection margins. However, many of these resections are

66

complex and may require extensive vascular dissection or reconstruction.5-10

EP

TE D

60

Multidisciplinary approaches to the treatment of STS have been previously advocated for,

68

and the involvement of a vascular surgical team in the management of STS has been associated

69

with decreased morbidity and improved outcomes.7-12 This study was performed to review the

70

clinical results achieved following surgical resection of soft tissue sarcomas undertaken by a

71

multidisciplinary team, including vascular surgery, orthopedic oncology, radiation oncology, and

72

medical oncology teams at a single academic tertiary medical center.

73

AC C

67

ACCEPTED MANUSCRIPT 5 74

Methods A retrospective review of the surgical treatment of soft tissue sarcomas at a single

76

academic tertiary medical center was performed. All surgical cases for soft tissue sarcoma

77

performed in conjunction with both orthopedic and vascular surgery teams at Cooper University

78

Hospital between July 1, 2012 and January 31, 2015 were reviewed. Cases with a confirmed

79

histologic diagnosis of sarcoma were included. Any cases without a final histologic diagnosis of

80

sarcoma were excluded. The Institutional Review Board of Cooper University Hospital reviewed

81

this study and approval was waived, as all patient data was de-identified.

SC

RI PT

75

The beginning of the study period marked the institution of a dedicated orthopedic

83

oncology center at Cooper University Hospital, establishing a partnership between the

84

institution’s Cancer Institute and Bone and Joint Institute. This relationship coincided with the

85

addition of a specialized cancer treatment center in partnership with MD Anderson Cancer

86

Center, an academic comprehensive cancer program. The multidisciplinary STS team at Cooper

87

University Hospital included orthopedic and vascular surgery, as well as team members from the

88

departments of medical oncology, diagnostic radiology, interventional radiology, pathology, and

89

radiation oncology.

EP

TE D

M AN U

82

The aim of vascular surgical intervention in this series was to preserve adequate flow to

91

the affected extremity. In patients requiring vascular repair or reconstruction, autologous conduit

92

from a non-affected limb was preferred, with plan for extra-anatomic tunneling if bypass was

93

needed. Primary amputation of an extremity was reserved for patients that would be left with a

94

non-functional limb after adequate resection of the tumor. Patients were seen and evaluated in

95

both the orthopedic and vascular surgical offices with appropriate preoperative imaging to

96

determine the extent of the disease as well as the likelihood of vascular reconstruction. Those

AC C

90

ACCEPTED MANUSCRIPT 6 97

patients in whom vascular reconstruction seemed likely also underwent vein mapping of all

98

extremities to determine the quality of autologous conduit. The main outcomes reviewed included the type of vascular intervention performed and

100

peri-operative mortality. Secondary outcomes reviewed included peri-operative morbidity

101

including wound complications, amputation, recurrence, tumor size, operative time, and

102

estimated blood loss (EBL).

RI PT

99

104

SC

103 Results:

A total of 63 patients with 66 surgical resections performed for STS were identified

106

during the study period. The indication for a combined orthopedic oncology/vascular surgery

107

intervention was the presence of a tumor immediately adjacent to, or directly involving, major

108

neurovascular bundles. Most resections performed involved the lower extremity (78.8%), with

109

upper extremity and pelvic resections accounting for a much smaller proportion of procedures

110

performed (9.1% and 12.1%, respectively). (Table 1) No patients died during the perioperative

111

period. Mean procedure time was 155 min, ranging from 27 min to 843 min. The procedure that

112

took 843 minutes required a free flap by plastic surgery. Average blood loss was 276 mL,

113

ranging from 5 mL to 2,000 mL.Sixteen of the sixty-six resections (24.2%) required vascular

114

intervention beyond assistance with exposure and vessel exploration. The most common

115

intervention was ligation of a vessel in 10 patients (62.5%). Two patients (12.5%) underwent

116

arterial bypass, one femoral to popliteal arterial bypass and one below knee popliteal to posterior

117

tibial arterial bypass. Four patients (25%) underwent primary repair of a vessel. (Figure 1) In

118

those patients requiring bypass, contralateral reversed great saphenous vein was utilized for the

119

reconstruction. The bypasses were tunneled outside of the area of oncologic resection.

AC C

EP

TE D

M AN U

105

ACCEPTED MANUSCRIPT 7 A total of seven patients underwent primary amputation. This included two hindquarter

121

amputations (28.6%), two hip disarticulations (28.6%), two transfemoral amputations (28.6%),

122

and one forequarter amputation (14.2%). Three patients experienced local recurrence and

123

required further surgery. Two patients with recurrence required repeat wide resections and one

124

patient with recurrence required transfemoral amputation. All three patients requiring further

125

surgery had large lower extremity sarcomas, two pleiomorphic sarcomas and one soft tissue

126

chondrosarcoma. The volumes of these tumors at the time of index resection were 3,740 mL,

127

1,805 mL, and 593 mL respectively.

SC

RI PT

120

Eleven patients (17.7%) experienced post-operative wound-related complications. These

129

complications were most frequent in patients requiring hip disarticulation (100%) or

130

hemipelvectomy (50%). Superficial skin and soft tissue wound infections were the most common

131

complication, accounting for 54.5%. One superficial wound complication was related to disease

132

recurrence causing skin ulceration that required an above knee amputation. Three deep soft tissue

133

infections were observed, accounting for 27.3% of wound complications. Both hip

134

disarticulations performed during this study resulted in superficial hip infections and one leg

135

resection resulted in a large defect that was unable to be closed and was not a candidate for flap

136

coverage that ultimately required an above knee amputation. Other complications included one

137

seroma and one rotational flap necrosis. (Figure 2)

139 140

TE D

EP

AC C

138

M AN U

128

Discussion

Soft tissue sarcomas are a diverse group of malignancies comprising of at least 80

141

different subtypes with varying presentations, behaviors, and outcomes. Though a relatively

142

uncommon malignancy, accounting for less than 1% of all adult malignancies in the US

ACCEPTED MANUSCRIPT 8 annually, STS represent an aggressive disease with nearly half of all subtypes malignant at

144

diagnosis with high metastatic potential, and the remainder of all subtypes acting locally

145

aggressive. As for all solid tumors, complete excision with adequate margins is the critical

146

surgical tenet for STS.1-4

RI PT

143

Unplanned sarcoma excision, without implementation of necessary surgical margins or

148

without appropriate local and systemic staging, can lead to residual disease or contamination of

149

surrounding structures, which may portend significantly worse outcomes for the patient.

150

Unfortunately, many patients may undergo resection or biopsy before referral to specialized

151

treatment centers. Given the heterogeneity of these tumors and the relatively rare nature of the

152

disease, most accept that a multidisciplinary setting with specialized oncologic centers is the best

153

practice for management of STS, ideally before resection is attempted.3,5,13

M AN U

SC

147

While wide excision with appropriate margins constitutes ideal treatment of STS, this

155

may lead to undesirable functional outcomes, especially in extremities. Historically, fully one-

156

third of patients with STS of the extremity underwent amputation for curative treatment. The rate

157

of primary amputation decreased to 15-20% during the mid-1980s to 1990s as wide resection

158

was combined with adjuvant or neo-adjuvant radiation.6 A push towards limb-sparing surgery,

159

particularly for STS of the extremity, comes with the added complexity of managing

160

neurovascular structures, leading to the inclusion of vascular surgeons in the multidisciplinary

161

care of patients with STS.7-12,14

EP

AC C

162

TE D

154

Experience detailing outcomes with major vascular resection and reconstruction is

163

limited with most reports describing small cases series.9,10 Schwarzbach et al. reported their

164

experience with 21 patients undergoing vascular resection during excision of extremity STS.

165

Eight patients (38.1%) underwent arterial reconstruction only and 12 patients (57.1%) underwent

ACCEPTED MANUSCRIPT 9 combined arterial and venous reconstruction. Of these patients, 57.2% experienced surgical or

167

wound morbidity, one-third required reoperation including two patients who needed revision of

168

their bypass. One patient died of pulmonary embolism in the peri-operative period, leading to a

169

mortality rate of 5%. At the end of the follow-up period, seven (35%) arterial bypasses had

170

occluded, resulting in two- and five-year primary patency rates of 58.3%. Venous bypass patency

171

was worse, with occlusion occurring in 5 patients (41.7%). However, limb salvage rates were

172

good, 94.1% at 5 years, with only one patient requiring a hemipelvectomy due to local

173

recurrence in the proximal thigh.7

SC

RI PT

166

Mogannam et al. advocated for early involvement of vascular surgical teams in the

175

planning and performance of oncologic resections. They reported their experience in 21 cases

176

over a seven-year period. Eleven cases (52%) had pre-operative vascular surgical consultation

177

and ten patients had urgent/emergent intraoperative vascular consultation. Complete resection

178

was achieved in 10 of 11 cases with pre-operative vascular surgical involvement (91%), while

179

only 70% of patients with intraoperative vascular surgical involvement achieved a complete

180

resection, though this was not statistically significant. Overall, six patients had vascular injury

181

requiring repair, five of which occurred in patients with urgent vascular surgical consultation,

182

which was statistically significant (P = .038). Estimated blood loss was also greater in patients

183

with urgent vascular consultation, 1,545 mL vs. 436 mL (P = .22). There was a trend towards

184

better survival in patients who had preoperative vascular surgical consultation. Additionally, this

185

study highlighted the added benefit of exposure to more open cases for vascular surgical trainees

186

in an era of increasing endovascular procedures and diminishing open surgical experience.11

AC C

EP

TE D

M AN U

174

187

Our results mirror those previously described with a moderate level of surgical morbidity,

188

mostly related to wound complications in nearly 18% of the patients in our series. However,

ACCEPTED MANUSCRIPT 10 more than half of those complications were superficial wound complications and self-limited

190

with adjunctive wound care and antibiotic management. Vascular surgical reconstructions were

191

also uncommon, and of the six patients requiring bypass or primary repair of vessels, only one

192

patient experienced a wound complication. Patients requiring vascular bypass did have longer

193

than average operative times (241 and 351 minutes) but did not experience any perioperative

194

complications and were discharged home at postoperative days four and six. The two patients

195

undergoing bypass were maintained on aspirin 81mg daily and followed up in the vascular

196

surgical office with surveillance duplex of the bypass at 1 month, 3 months, 6 months, then

197

annually. To date, both bypasses have remained widely patent without additional intervention.

M AN U

SC

RI PT

189

198 199

Conclusion

STS comprise a heterogeneous yet infrequent malignancy in which the mainstay of

201

treatment is complete surgical excision. As the focus of treatment of STS shifts towards

202

achieving successful resection with acceptable functional outcomes, as well as high rates of limb

203

salvage, it is apparent that a multidisciplinary approach is necessary to achieve this goal.

204

Multiple groups have shown improved outcomes with the inclusion of various disciplines in the

205

treatment of STS. As multidisciplinary teams become the mainstay for the treatment of STS,

206

hospital groups must evaluate who should be included in the treatment team and what role each

207

participant should play.

EP

AC C

208

TE D

200

The inclusion of vascular surgeons as part of the multidisciplinary team, especially in the

209

preoperative planning and preparation, has been shown to improve the treatment of soft tissue

210

sarcomas by optimizing complex resections that may require involved vascular control or

211

reconstruction. Additionally, including vascular surgery as part of the multidisciplinary team

ACCEPTED MANUSCRIPT 11 may provide trainees with a broader open case experience, both for vascular exposures as well as

213

for interventions. This review of our institutional experience with a multidisciplinary approach to

214

STS after the inception of a dedicated oncologic orthopedic service within a specialized cancer

215

treatment paradigm has shown promising outcomes with respect to peri-operative mortality,

216

disease recurrence, amputation, and peri-operative morbidity.

RI PT

212

Based on our experience and that of other groups reporting outcomes for STS, we

218

recommend a multidisciplinary evaluation of patients undergoing surgical resection of STS that

219

includes the involvement of orthopedics, vascular surgery, oncology, pathology, and radiology

220

when possible. Additionally, full radiologic evaluation of the patients preoperatively, including

221

vein mapping, is important for anticipating the likelihood of vascular surgical reconstruction as

222

well as planning the type and location of reconstruction or bypass. Autologous conduit from the

223

contralateral limb is preferred, and both arterial and venous reconstructions should be performed

224

when feasible. Additionally, we recommend tunneling outside of the area of resection for bypass

225

procedures given the rate of wound infection and surgical site complications.

TE D

M AN U

SC

217

The limitations of our review include the retrospective nature, short follow-up, and small

227

overall number of cases with vascular surgical intervention. Further study is needed to determine

228

the added value of specialty surgeons in the multidisciplinary care of STS as well as the value of

229

these cases for vascular trainees.

AC C

230

EP

226

ACCEPTED MANUSCRIPT 12 231

References

232 [1] Massarweh N, Dickson P, Anaya D. Soft tissue sarcomas: Staging principles and

234

prognostic nomograms. J Surg Onc 2015; 111: 532-9.

235

RI PT

233

[2] Brennan M, Antonescu C, Moraco N, Singer S. Lessons learned from the study of 10,000

237

patients with soft tissue sarcoma. Ann Surg 2014; 260: 416-422.

SC

236

238

[3] Kneisl J, Coleman M, Raut C. Outcomes in the management of adult soft tissue sarcomas.

240

J Surg Onc 2014; 110: 527-538.

241

M AN U

239

[4] Coindre J, Terrier P, Gillou L, Le Doussal V, Collin F, Ranchere D, et al. Predictive value of

243

grade for metastasis development in the main histologic types of adult soft tissue sarcomas:

244

A study of 1240 patients from the French Federation of Cancer Centers sarcoma group.

245

Cancer 2001; 91: 1914-1926.

EP

246

TE D

242

[5] Chao A, Mayerson J, Chandawarkar R, Scharschmidt T. Surgical management of soft

248

tissue sarcomas: Extremity sarcomas. J Surg Onc 2015; 111: 540-5.

249

AC C

247

250

[6] Williard W, Hadju S, Casper E, Brennan M. Comparison of amputation with limb-sparing

251

operations for adult soft tissue sarcoma of the extremity. Ann Surg 1992; 215: 269-275.

252

ACCEPTED MANUSCRIPT 13 [7] Schwarzbach M, Hormann Y, Hinz U, Bernd L, Willeke F, Mechtersheimer G, et al.

254

Results of limb-sparing surgery with vascular replacement for soft tissue sarcoma in the

255

lower extremity. J Vasc Surg 2005; 42: 88-97.

256

RI PT

253

[8] Emori M, Hamada K, Omori S, Joyama S, Tomita Y, Hashimoto N, et al. Surgery with

258

vascular reconstruction for soft-tissue sarcomas in the inguinal region: Oncologic and

259

functional outcomes. Ann Vasc Surg 2012; 26: 693-9.

260

SC

257

[9] Muramatsu K, Ihara K, Miyoshi T, Yoshida K, Taguchi T. Clinical outcome of limb-salvage

262

surgery after wide resection of sarcoma and femoral vessel reconstruction. Ann Vasc Surg

263

2011; 25: 1071-7.

M AN U

261

264

[10] Song T, Harris J, Raghavan S, Norton J. Major blood vessel reconstruction during

266

sarcoma surgery. Arch Surg 2009; 144: 817-822.

267

TE D

265

[11] Mogannam A, de Paz C, Sheng N, Patel S, Bianchi C, Chiriano J, et al. Early vascular

269

consultation in the setting of oncologic resections: Benefit for patients and a continuing

270

source of open vascular surgical training. Ann Vasc Surg 2015; 29: 810-5.

AC C

271

EP

268

272

[12] McGoldrick N, Butler J, Lavelle M, Sheehan S, Dudeney S, O’Toole G. Resection and

273

reconstruction of pelvic and extremity soft tissue sarcoma with major vascular

274

involvement: Current concepts. World J Orthop 2016; 7: 293-300.

275

ACCEPTED MANUSCRIPT 14 276

[13] Charoenlap C, Imanishi J, Tanaka T, Slavin J, Ngan S, Changer S, et al. Outcomes of

277

unplanned sarcoma excision: Impact of residual disease. Cancer Med 2016; 5: 980-8.

278 [14] Muller D, Beltrami G, Scoccianti G, Frenos F, Capanna R. Combining limb-sparing

280

surgery with radiation therapy in high-grade soft tissue sarcoma of extremities—Is it

281

effective? Eur J Surg Oncol 2016; 42: 1057-1063.

AC C

EP

TE D

M AN U

SC

282

RI PT

279

ACCEPTED MANUSCRIPT 15 Figure Legends

284

Figure 1: Intervention Performed

285

Figure 2: Wound Complications

AC C

EP

TE D

M AN U

SC

RI PT

283

ACCEPTED MANUSCRIPT

Cases

Lower Extremity

Arterial

EBL

Range

Range

(Average) mL3

(Average) mL

43

5 – 9,000 (1,174)

5 – 600 (112)

2

720 – 1,155

200 – 1,000

SC

Involvement

Tumor Size

RI PT

Table 1: All cases performed Location Vascular

(614)

(600)

24 – 2,280 (721)

50 – 550 (250)

Exploration

Primary Repair

4

of Vessel Ligation of

3

Vessel Arterial

3

TE D

Upper Extremity

M AN U

Arterial Bypass

Exploration Ligation of

Pelvis

EP

Vessel

Arterial

3

4

AC C

Exploration

Ligation of

50 – 300 (217)

180 – 3,016

100 – 200 (167)

(1,325) 180 – 3,060

50 – 500 (267)

(1,280) 28 – 11,934

50 – 1,500 (788)

(3,248) 4

Vessel

Total

49 – 1,620 (655)

66

980 – 36,300

600 – 2,000

(9,969)

(1,525)

5 – 36,300

5 – 2,000 (276)

(1,776)

ACCEPTED MANUSCRIPT

Table 1: All cases performed Vascular Involvement

Cases

Tumor Size Range (Average) mL3

EBL Range (Average) mL

Lower Extremity

Arterial Exploration Arterial Bypass Primary Repair of Vessel Ligation of Vessel

43 2 4 3

5 – 9,000 (1,174) 720 – 1,155 (614) 24 – 2,280 (721) 49 – 1,620 (655)

5 – 600 (112) 200 – 1,000 (600) 50 – 550 (250) 50 – 300 (217)

Upper Extremity

Arterial Exploration Ligation of Vessel

3 3

180 – 3,016 (1,325) 180 – 3,060 (1,280)

100 – 200 (167) 50 – 500 (267)

Pelvis

Arterial Exploration Ligation of Vessel

4 4

28 – 11,934 (3,248) 980 – 36,300 (9,969)

50 – 1,500 (788) 600 – 2,000 (1,525)

66

5 – 36,300 (1,776)

5 – 2,000 (276)

AC C

EP

TE D

SC

M AN U

Total

RI PT

Location

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT