Wound complications following pre-operative radiotherapy for soft tissue sarcoma

EJSO 2002; 28: 75–79 doi:10.1053/ejso.2001.1213, available online at http://www.idealibrary.com on

Wound complications following pre-operative radiotherapy for soft tissue sarcoma T. Kunisada, S. Y. Ngan, G. Powell and P. F. M. Choong Bone and Soft Tissue Sarcoma Unit, St. Vincent’s Hospital and Peter MacCallum Cancer Institute, Level 3 Daly Wing, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia

Aims: We analysed wound complications in 43 patients with soft tissue sarcoma who were treated with combined pre-operative radiotherapy and surgery. Methods: All patients received the same protocol of pre-operative radiotherapy at our institution. Results: Thirty-six (84%) patients developed acute skin toxicity following radiotherapy. After wide local excision, 15 patients required primary soft tissue reconstruction with vascularized muscle transfer and four patients underwent free skin flap to enable wound closure as part of their primary surgery. Nineteen patients (44%) developed postoperative wound complications including 10 (23%) patients who required an additional surgical procedure. Four (27%) patients developed flap necrosis in a group of 15 who underwent primary vascularized soft tissue transfer. All required a second vascularized muscular flap. One elderly patient, who had grade 3 acute radiation skin toxicity, had an arterial graft and total hip arthroplasty for a femoral artery aneurysm and an avascular necrosis of the hip, respectively. In our series, age ([40 years) was the only impact factor influencing wound complication after surgery following radiotherapy (P=0.06). Conclusions: Site of tumour, radiation field size, surgical resection volume, grade of acute radiation toxicity, comorbidity, and smoking were not demonstrated to have predictive value in wound complication following preoperative radiotherapy. Although previous papers suggested that vascularized soft tissue transfer could be useful reducing wound morbidity, our results could not confirm this.  2002 Harcourt Publishers Ltd Key words: wound complication; soft tissue sarcoma; pre-operative radiotherapy; surgery.

INTRODUCTION Soft tissue sarcoma is a rare solid tumour arising from connective tissue. Amputation was previously the main surgical treatment of extremity soft tissue sarcoma, but limb-sparing surgery now offers good local control with superior functional results than amputation. Occasionally, adequate surgical margins may not be possible because of the proximity of the tumour to vital neuro-vascular structures, and the combination of local radiotherapy with surgery has proven to be effective for local control while producing favourable local functional results.1–3 Preoperative radiotherapy for soft tissue sarcoma has theoretical advantages over post-operative radiotherapy,4,5 though the timing of radiation remains a controversial issue.

Correspondence to: Professor Peter F. M. Choong, Department of Orthopaedics, St. Vincent’s Hospital, Level 3 Daly Wing, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. Tel: +61-3-9288-3980; Fax: +61-3-9416-3610; E-mail: [email protected] 0748–7983/02/010075+05 $35.00/0

Wound morbidity is an important factor when resecting soft tissue sarcoma, because it may be necessary to resect large volumes and areas of soft tissue overlying a tumour. This is particularly relevant when surgery is combined with radiotherapy. Some authors have discussed wound complications in the context of multidisciplinary adjuvant therapy and demonstrated that radiotherapy was an important risk factor influencing wound morbidity.6,7 In this study, we highlight woundhealing complications in patients with soft tissue sarcoma treated with pre-operative radiotherapy.

PATIENTS AND METHODS Patients Forty-three patients with soft tissue sarcoma underwent surgery (42 limb sparing surgery and one hindquarter amputation) at our institution between 1996 and 2000 following the same protocol of pre-operative radiotherapy. There were 28 men and 15 women, with  2002 Harcourt Publishers Ltd

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T. KUNISADA ET AL.

Table 1 Preoperative grading of skin morbidity following radiotherapy according to RTOG Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

No change over baseline Follicular. Faint or dull erythema: epilation: dry desquamation: decreased sweating Tender or bright erythema: patchy moist desquamation: moderate oedema Confluent. Moist desquamation other than skin folds: pitting oedema Ulceration. Haemorrhage or necrosis

a median age of 49 years (range 16–82 years). Twenty patients were referred to our institute before or after an excisional biopsy at the referring institution. No patient had metastases at diagnosis. Eleven patients had a smoking history and nine patients showed a comorbidity (diabetes or vascular disease).

Tumours Histological diagnosis consisted of 21 malignant fibrous histiocytoma (MFH), 11 liposarcoma, five synovial sarcoma, two leiomyosarcoma and four others. There were 30 grade 4 tumours, one grade 3, 11 grade 2 and one desmoid tumour. Twenty-eight tumours were located in the lower leg, eight in the upper arm, and seven in the trunk wall. At the time of diagnosis, all tumours were characterized by pathologists in our institution. The tumour size was defined as the longest diameter of the tumour measured on MRI, showing a median tumour size of 7.0 cm (range 1.5–28.0).

Radiotherapy The regimen of pre-operative radiotherapy included 50.4 Gy given in 28 fractions over 5 weeks to a volume of the tumour with a margin of uninvolved tissue determined by computed tomography and/or magnetic resonance imaging (MRI). One patient, who had had radiotherapy previously for another cancer treatment, received a total dose of 48 Gy. Median field length of radiation was 24 cm (range 11–36). Acute radiation skin toxicity was evaluated using Radiation Therapy Oncology Group (RTOG) acute radiation toxicity criteria8 (Table 1). No patient underwent pre-operative chemotherapy. The surgery was performed at least 3 weeks (median 35 days, range 22–54) after the completion of pre-operative radiotherapy. No patient received intra-operative radiation, brachytherapy, or additional post-operative radiotherapy. Surgical specimens were examined microscopically to evaluate the surgical margin. Three patients were treated with palliative chemotherapy subsequently at the time of diagnosis of distant metastasis.

Surgery Excision or re-excision with wide margin was performed at our institution for all patients. One patient underwent amputation with wide margin. Post-operative pathological examination showed that all surgical specimens had negative margins. Median volume of surgically resected specimen was 133.8 cm3 (range 16.0–1393.3). A skin ellipse was included with the resected specimen in 26 patients. These were assessed from pathological reports. One patient, who had a malignant schwannoma in the buttock, was compelled to undergo hindquarter amputation because of the proximity of vital neuro-vascular structures even after pre-operative radiotherapy. This patient was excluded from analysis of surgically resected volume and skin. Fifteen patients required soft tissue reconstruction with vascularized muscle transfer to enable wound closure. Nine of these patients had previous excisional biopsies at referral institution. Four patients underwent free split skin graft. Four patients had en bloc excision with adjacent bone and had bone reconstructions with proximal femur tumour endo-prosthesis, allograft, vascularized fibula graft and intramedullary rod alone.

Statistical analysis We studied the influence of the following factors on post-operative wound morbidity following pre-operative radiotherapy; age, field size of radiation, duration from end of radiotherapy to surgery, primary or secondary (referred before or after excisional biopsy) surgery, smoking history, comorbidity (diabetes/vascular disease), acute radiation skin toxicity, wound closure using vascularized tissue transfer, tumour size, volume of surgically resected specimen, surgically resected skin, tumour site, and histology type. We compared each of these factors with the presence of post-operative wound complications. Wound complication that required second surgical procedure was regarded as major wound complication. Statistical differences between categorical variables were determined using chi-square tests or Fisher’s exact probability test. Test results with P<0.05 were regarded as significant.

RESULTS Thirty-six (84%) of 43 patients developed acute skin toxicity from pre-operative radiotherapy (23 grade 1, 11 grade 2, and 2 grade 3) (Table 2). There were 19 (44%) post-operative wound complications and 10 (23%) of those required second surgery for wound complication. In the group of 24 patients who were treated with primary closure without soft tissue reconstruction, 10 (42%) patients had wound complications, and five of them required second surgical

WOUND COMPLICATIONS FOLLOWING PRE-OPERATIVE RADIOTHERAPY

77

Table 2 Effect of categorical variables on wound complications in 33 patients Wound complications Age Ζ40 years [40 years Site Lower leg Upper limb Trunk Histology MFH Liposa Synovialsa Leiomyosa Others Tumour size Ζ8 cm >8 cm RT field length Ζ27 cm >27 cm Day from RT to surgery Ζ38 days >38 days Smoking Smoker Non-smoker DM/vascular disease Yes No Post-radiation skin grade 0 1 2 3 Initial surgery Our institute Referring institute Wound closure Primary Reconstruction Surgically resected volume <160 cm3 Ζ160 cm3 Surgically resected skin No Yes

Complication Yes No

P

Major complication Yes No

0.06 4 15

12 12

15 3 1

13 5 6

10 5 1 1 2

11 6 4 1 2

9 10

16 8

10 9

15 9

9 10

14 10

3 16

8 16

5 14

4 20

3 8 6 2

4 15 5 0

9 10

14 10

10 9

14 10

9 9

14 10

6 12

10 14

0.28 2 8

14 19

8 1 1

20 7 5

4 2 1 1 2

17 9 4 1 2

4 6

21 12

4 6

21 12

4 6

19 14

3 7

8 25

2 8

7 26

2 4 3 1

5 19 8 1

4 6

19 14

5 5

19 14

5 4

18 15

3 6

13 20

0.16

0.53

0.85

0.59

0.20

0.18

0.55

0.28

0.47

0.33

0.29

0.70

0.48

1.00

0.28

0.69

0.47

0.33

0.71

0.67

0.59

0.96

0.58

procedure, which composed of free skin graft for one patient and debridement alone in three patients. Another patient who required a second surgical procedure for wound complication showed a continuous serous discharge from the wound and lymphoedema of the left lower leg after definitive surgery. This patient had RTOG grade 3 radiation skin toxicity from pre-operative radiotherapy. Angiography suggested an aneurysm of the left femoral artery, which required artery graft with

P

0.74

wound debridement 3 months after initial surgery. He gradually developed right hip pain 1 year after arterial surgery and an X-ray and MRI showed femoral head collapse and osteoarthritis of the hip joint. A total hip arthroplasty was necessary 18 months after initial surgery. Two of four patients who underwent free split skin graft showed one delayed wound healing and one superficial infection. Both healed without any surgical procedure. Six (40%) of 15 patients who were treated

78 with primary vascularized soft tissue transfer showed wound complication. Four of those developed flap necrosis and all required a second vascularized muscular flap. One patient showed small wound edge necrosis that healed without further procedure and one patient showed partial wound dehiscence that required debridement. Of these four patients who had second muscular flap, three patients had previous excisional biopsies at the referral institution. All recovered after their second procedures without complication. Table 2 summarizes the results of wound morbidity of each factor. Age greater than 40 years correlated with higher wound complication rate (P=0.06). No other factor was associated with post-operative wound complication, nor major wound complication which required a second surgical procedure. Median follow up of all patients was 28 months (range 3–47). There was no local recurrence, but 12 patients developed metastases. At last follow-up, 30 patients continued to be disease free, three with no evidence of tumour after metastatectomy, eight alive with disease, one died of disease, and one died of other cause.

DISCUSSION Radiotherapy combined with adequate surgery is considered to be effective for local control of patients with resectable soft tissue sarcoma.2,9,10 In these studies, the standard of treatment has been resection with or without soft tissue reconstruction followed by radiotherapy. More recently, however, the timing of radiotherapy remains controversial. The practice of preoperative radiotherapy encourages a multidisciplinary team approach, with orthopaedic, radiation and medical oncologists, pathologists, radiologists, and nuclear physicians, formulating the most appropriate plan for the patient. There are a number of theoretical advantages with radiotherapy given pre-operatively. Tissue hypoxia is a major factor in radio-resistance. By giving radiation pre-operatively, it is delivered to an undisturbed field without the drawback of inevitable surgical-induced hypoxia from devascularization.11,12 The tumour is potentially more sensitive allowing a lower radiation dose to achieve an equivalent effect. Pre-operative radiotherapy also allows a smaller radiation volume and a lesser dose for the same tumour size compared with post-operative radiotherapy.13 It does not have to allow extra margins for possible surgical field contamination as in post-operative radiotherapy. A smaller radiation volume may translate into improved long-term functional results. However, pre-operative radiotherapy can lead to increased wound-healing problems after surgery. In this study, we reviewed our experience from 1996 of soft tissue sarcoma treated with pre-operative radiotherapy (50.4 Gy in 1.8 G/fraction) without neoadjuvant chemotherapy, and highlighted early wound-healing complications following limb-sparing surgery.

T. KUNISADA ET AL. Bujko et al.7 reported 42% wound complications in a group of 59 patients treated with pre-operative radiotherapy (average total dose 47.5 Gy, range 16–70) including some patients treated with chemotherapy. Major wound complications occurred in 20% requiring additional surgery. Peat et al.14 reported that 28% of 56 patients treated with only pre-operative radiotherapy (total dose 50 Gy in 25 fractions over 5 weeks) and surgery alone developed major wound complications. Our result of 44% wound complications including 23% major wound complications was similar to other preoperative radiation series. A study on combined surgery and brachytherapy demonstrated 26% wound complications with 16% major complications.15 This suggested better results with wound problems than preoperative radiation series. Post-operative radiotherapy showed even better results (6–8%) of wound complications than pre-operative radiotherapy.12,16 Breakdown of the surgical wound is uncommon once it is healed, and post-operative radiotherapy is seldom started before the surgical wound is reasonably healed. However, Saddegh and Bauer17 reported that surgery alone for soft tissue sarcoma demonstrated 40% wound complications with 16% major wound complications. Thus, many authors have reported differing wound healing complication rates, which range between 20–40%, of patients undergoing sarcoma surgery with various adjuvant therapy.18–21 Although our results of wound complication following pre-operative radiotherapy were similar to previous papers, the only randomized study performed demonstrated a higher rate of wound complication with pre-operative radiotherapy than post-operative radiotherapy.22 However, in our series a higher rate of early complication did not lead to long-term wound problems nor amputations. Moreover, radiotherapy followed by second wide excision did not increase the complication rate, indicating that radiotherapy could be applied before definitive surgery for this situation. Various risk factors such as age, tumour location, tumour site, and the resection diameter, may influence wound complication rates in the treatment of soft tissue sarcoma.6,7,14,18,23 However, there were very few reports regarding the impact on wound healing of patients treated with pre-operative radiotherapy followed by surgery alone. In our series of patients treated with pre-operative radiotherapy and surgery alone, older age (Ζ40 years) was the only factor associated with wound complications. Specifically, smoking, diabetes, vascular disease, acute radiation toxicity or tumour size did not affect wound healing. Four of 15 patients who underwent vascularized soft tissue transfer developed flap necrosis in the immediate post-operative period and required a second vascularized re-transfer. The relatively high complication rate was in contrast to the other reports.14,24,25 An explanation was the sites of the flaps. Three of these flaps were performed

WOUND COMPLICATIONS FOLLOWING PRE-OPERATIVE RADIOTHERAPY at the lateral aspect of the ankle joint, posterior side of the elbow joint and lateral side of the knee joint, raising the question as to whether the involved joint should be immobilized for a period of time after flap reconstruction to minimize trauma to the vascular pedicle. The early timing of flap failure implicates technical problems rather than pre-operative radiotherapy as the cause of failure. In our series, an 81-year-old patient, who had grade 3 acute radiation toxicity, developed an aneurysm of the femoral artery post-operatively which required artery graft. His course was further complicated by avascular necrosis of the femoral head. This demonstrates the potential morbidity of radiotherapy to bone and soft tissue near a joint in elderly patients. It highlights the need for gentle tissue handling after pre-operative radiation in particular in the aged. A rare complication of radiotherapy is radiationinduced sarcoma. If radiotherapy is given pre-operatively, and the area irradiated is excised, the question remains as to whether this would be better than following postoperative radiation treatment where the total volume of irradiated tissue is left in situ. There is insufficient experience in the literature to comment further on this very rare occurrence. While our paper deals specifically with resectable tumours, we recognize that complex unresectable cases require consideration of extraordinary methods such as hyperthermic isolated limb perfusion with tumour necrosis factor and melphalan if an attempt at salvage surgery is to be made. Discussion of this, however, is beyond the scope of this paper. In the final 18 months of the study period in this 4-year series, no major wound complications were encountered, indicating that continued improvement of the results can be expected with further experience, and when combined with the benefits, which include smaller radiation treatment volume, potentially enhanced resectability by decreasing mass size and inciting a fibrous capsule to form, and a theoretical decreased risk of tumour implantation, our preferred method of treatment is pre-operative radiotherapy followed by wide resection surgery.

6. 7. 8.

9.

10.

11. 12.

13.

14. 15.

16. 17. 18. 19. 20.

21.

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Accepted for publication 6 September 2001