Journal of Surgical Oncology 2011;103:175178

Neoadjuvant Radiotherapy and Reconstruction Using Autologous Vein Graft for the Treatment of Inferior Vena Cava Leiomyosarcoma
GITONGA MUNENE,
MD,

LLOYD A. MACK,

MD,

RANDY D. MOORE,

MD, AND

WALLEY J. TEMPLE,

MD*

Department of Surgery, Divisions of Surgical Oncology and General Surgery, University of Calgary and the Tom Baker Cancer Centre, Calgary, Alberta, Canada

Background and Objectives: Inferior vena cava (IVC) leiomyosarcomas are rare and are a relatively small subset of retroperitoneal sarcomas. The current approach is resection and ligation or reconstruction of the IVC. This study was undertaken to analyze the outcomes associated with the use of neoadjuvant radiotherapy and IVC reconstruction in the treatment of IVC leiomyosarcoma. Methods: A retrospective clinicopathological review of patients treated during a 10-year period. Results: Four patients were treated with neoadjuvant radiotherapy, median 47.5 Gy, all underwent margin negative resection with 75% of the tumors being high grade and all patients requiring resection of adjacent organs. Reconstruction of the IVC was performed with an autologous supercial femoral vein graft. There were no mortalities and the morbidity rate was 50%. At a median follow up of 37 months; two patients had a patent IVC, no patients had a local recurrence, and one patient developed a distant metastases treated successfully with metastectomy. Conclusions: Neoadjuvant radiotherapy and resection of the IVC leiomyosarcoma resulted in 100% local control, and all patients are alive at median follow up of 37 months. IVC reconstruction with the supercial femoral vein is safe and associated with acceptable short and long term morbidity. J. Surg. Oncol. 2011;103:175178. 2010 Wiley-Liss, Inc.

KEY WORDS: neodjuvant radiotherapy; surgery; retroperitoneal sarcoma

INTRODUCTION
Inferior vena cava (IVC) sarcomas originating from the smooth muscle media constitute only 2% of all leiomysosarcomas, and are the most common malignant tumors of the IVC [1]. IVC leimyosarcomas like other retroperitoneal sarcomas are treated with curative resection, but have a high propensity to recur after surgery [2]. Radiation therapy has not been shown to increase the overall survival in leiomyosarcomas just as is the case in retroperitoneal sarcomas, but there is a suggestion that radiation may improve local control [3,4]. Due to the rarity of this disease, most published reports regarding the treatment of IVC leimyosarcomas are from small case series, and case reports, with fewer than 15 patients reported in the literature treated with preoperative radiotherapy [57]. Once the IVC is resected there is considerable controversy regarding the need and technique for reconstruction. Some authors have suggested that IVC ligation is well tolerated and to attempt reconstruction or replacement is unnecessary. Others argue that IVC ligation can lead to signicant morbidity related to lower extremity edema and favor reconstruction in all patients with a patent IVC preoperatively. Techniques for reconstruction vary and include interposition grafts or venoplasty [8,9], and the material used for the graft also varies from prosthetic grafts to allograft [8,10,11]. For the past decade we have treated all patients with retroperitoneal sarcomas at our institution with neoadjuvant radiotherapy followed by curative resection. The preference has been to attempt reconstruction in all cases and the technique for reconstruction of the IVC has been with harvested supercial femoral vein allograft. Here we describe our experience with neoadjuvant radiation and curative resection of IVC leiomyosarcomas with IVC reconstruction using autologous vein.

and surgical resection with curative intent from January 2001 to October 2009 at our institution. Pathology reports were reviewed to conrm that the tumor was of IVC origin, all other retroperitoneal leiomyosarcomas were excluded. All patients underwent preoperative CT scan and/or MRI, and a CT guided biopsy was obtained prior to initiating radiotherapy. The clinical records were reviewed; demographic data and the following variables were collected: presenting signs and symptoms at diagnosis, preoperative work up, location of tumor, neoadjuvant radiotherapy, surgical technique, morbidity, and mortality. The tumor location was classied into: type 1 (from right Atrium to hepatic vein conuence), type 2 (from hepatic vein conuence to renal veins) and type 3 (below renal veins). The following morbidities were included in our analyses renal failure, wound infection, deep vein thrombosis, pulmonary embolus, and need for reoperation. Post-operative data such as extent of lower extremity edema, recurrence and overall survival were also obtained. Specimens were divided into grades based on the level of differentiation, mitotic rate, and areas of necrosis after being reviewed by a pathologist with specialized training in soft tissue sarcoma [12,13]. Patients were seen in the cancer clinic 3 months after discharge and CT scan was performed every 6 months. Post-operative CT scans were evaluated for vena cava patency and for detection of recurrence. The extent of lower extremity edema was dened as: minimal (no impairment) and persistent severe (persistent functional impairment). Overall survival was calculated from the date of surgery to date of death or last follow up.

*Correspondence to: Walley J. Temple, MD, Division of Surgical Oncology, Tom Baker Cancer Centre, 133129th St NW, Calgary, AB, Canada T2N 4N2. Fax: 1-403-521-3744. E-mail: walley.temple@albertahealthservices.ca Received 9 August 2010; Accepted 22 October 2010 DOI 10.1002/jso.21798 Published online 28 December 2010 in Wiley Online Library (wileyonlinelibrary.com).

MATERIALS AND METHODS

A retrospective review was performed on all patients diagnosed with IVC leiomyosarcoma and treated with preoperative radiotherapy

2010 Wiley-Liss, Inc.

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Multimodal Treatment
Our protocol has been previously described but briey, after consultation with the radiation oncologist, all patients with potentially signicant radiation toxicity to adjacent organs and bowel underwent laparotomy for placement of one or two saline lled tissue expanders to displace the small bowel or protect adjacent organs [4]. With the more recent emergence of conformal 3-D radiotherapy the need for the spacer has diminished. Two weeks after placement of tissue expanders, standard pre-operative treatment dose of 4,5005,000 cGy was given in daily fractions of 180200 cGy for 25 sessions. Six to 8 weeks after the completion of radiotherapy therapy, denitive resection was performed. IVC resection was performed in all cases and reconstruction was performed using the supercial femoral vein. The supercial femoral vein was harvested from the profunda vein to the highest genicular above the knee, and was used either as patch venoplasty or as an interposition graft. An attempt was made in all cases to cover the vascular anastomosis with a pedicled omental ap. Drains were routinely inserted; deep vein thrombosis and antibiotic prophylaxis were administered according to institutional recommendations.

RESULTS
Patient characteristics are shown in Table I. Three of four patients were women (75%), with a median age of 48 years. All patients presented with abdominal pain for an average of 1 month, and one patient presented with abdominal pain associated with signicant weight loss. All patients underwent a CT scan preoperatively (Fig. 1) and the diagnosis was established in four out of four patients by CT guided biopsy. On preoperative imaging, the IVC was patent in all cases, but was noted to be partially obstructed in two patients without any evidence of lower extremity edema. There were no complications related to spacer placement and all patients completed the prescribed dose of radiotherapy, median dose 47.5 Gy. No appreciable increase or decrease in size of the tumor was noted in any patients after radiotherapy. After preoperative radiotherapy all four patients underwent exploratory laparatomy and resection. In three patients a midline incision was used and in one a thoracoabdominal incision. In all cases the resection involved additional organs including the aorta (one patient), kidney (three patients), adrenal (one patients), colon (one patient), and partial duodenectomy (one patient). The aorta reconstruction was performed with a prosthetic Dacron graft. The IVC reconstruction was performed by harvesting the supercial femoral vein and this was used as a patch venoplasty in three cases and in one patient as an interposition graft (Table II). All patients received systemic heparin intraoperatively and post-operatively, the median estimated blood loss was 900 cc (400 1,250), and median operative time was 515 minutes (600420 minutes). The median size of the tumor was 8 cm and all patients had a microscopically negative resection (R0). Tumor grade was high in three patients and was found to be low grade in one patient. On pathological analysis the growth of the tumor was found to be extraluminal in all but one case. No lymph nodes were found to contain neoplastic disease. The median length of stay was 21.5 days and there were no perioperative deaths. A groin hematoma developed in one patient at the site
TABLE I. Patient Characteristics Patient 1 2 3 4 Age 47 59 49 46 Gender F F M F Symptoms Abdominal pain Abdominal pain Pain Pain, weight loss Type 2 2 2 2 IVC patency Partial Patent Patent Partial RTX (Gy) 45 45 50 50

Fig. 1.

Preoperative CT scan showing IVC leiomysosarcoma.

of the vein harvest requiring groin exploration and ligation of bleeding vessel otherwise his hospital course was unremarkable. Post-operative ileus developed in one patient and was managed conservatively with nasogastric tube decompression and nutrition support. Post operatively anticoagulation was not standard. Three patients were treated with perioperative deep vein thromboprophylaxis and sent home with low dose aspirin. One patient with complete IVC replacement was discharged on Coumadin for 3 months after which it was discontinued. No episodes of pulmonary embolism or deep vein thrombosis were noted during hospitalization. Edema was minimal at the time of discharge in all patients. Post-operative surveillance CT scans were performed in all patients at 6-month intervals for the rst 3 years and then annually until the 5-year mark. Complete IVC thrombosis was noted in one patient, partial in one patient and the other two had no evidence of thrombosis. None of the patients had persistent severe edema, one patient required use of compression stockings after developing a deep vein thrombosis 4 years after surgery. At a median follow up of 37.5 months, one patient had developed distant metastases to the lung, and liver, and is alive at a follow up of 61 months. All other patients have no evidence of local recurrence or distant disease.

DISCUSSION
The primary treatment of IVC leimomyosarcoma is surgical resection which is possible in approximately 2/3 of the patients [2]. Our experience is consistent with most other reports regarding IVC

RTX, radiotherapy.

Journal of Surgical Oncology DOI 10.1002/jso

Neoadjuvant Radiotherapy, IVC Leiomyosarcoma

TABLE II. Tumor Characteristics Patient 1 2 3 4 Size (cm) 7 4 12.2 9 Grade Low High High High Growth Intraluminal Extraluminal Extraluminal Extraluminal Adjacent organs resected Aorta Right kidney, right adrenal Right kidney, right hemicolectomy, partial duodenectomy Right kidney, adrenal R0/R1 R0 R0 R0 R0

177

IVC repair Venoplasty Venoplasty Interposition graft Venoplasty

leiomyosarcoma with a higher incidence in women, most often being found between the hepatic vein and renal veins (type two) [8,14]. Resection of adjacent organs was required in all of our cases to achieve a complete macroscopic and microscopic resection which is comparable to most other series, where a need for adjacent organ resection occurred in 6083% of the patients [6,7,9,14,15]. Surgical margins have been shown to be predictive of local regional failure and overall survival in the treatment of retroperitoneal sarcomas [16,17], and some authors have advocated a complete resection of the IVC to achieve adequate surgical margins [11]. However an R0 resection was achieved in all the patients in our series even with partial IVC resections. The reason for this may be that in most cases the tumor grew extraluminally, the median size of tumor in our cohort was smaller than most reports and in the one patient in which an intraluminal component was present it was measured at 1.8 cm. The rate of high grade tumors in our population was high at 75% and this is comparable to most series which report rates of 57.5100% [6,14]. The morbidity rate was comparable to most reports evaluating the surgical treatment of IVC leiomyosarcomas [5,14]. The prognosis of IVC leiomyosarcomas has been found to be equivalent or poorer in comparison to retroperitoneal sarcomas with most studies reporting a higher incidence of local and distant recurrences and lower overall survival [6,14]. The use of radiotherapy for treatment of retroperitoneal sarcomas may decrease local recurrence rates, and this is the basis for our decision to use adjuvant radiotherapy for leiomyosarcomas of the IVC [3,18]. To date, there has not been a trial that has shown a benet of preoperative radiotherapy versus postoperative radiotherapy in the treatment of retroperitoneal sarcoma; however the theoretical advantages of preoperative radiotherapy are: the tumor is better vascularized and therefore more radiosensitive, decreased area of treatment, better directed therapy, and associated with fewer complications compared to postoperative radiotherapy [19]. R0 resections in IVC leiomyosarcomas are achieved in 3367% of cases [5,7,14,15,20]; the addition of adjuvant radiotherapy may theoretically improve on the rates of R0 resection and/or decrease the recurrence associated with positive margins. In the treatment of IVC leiomyosarcomas, most studies have reported local recurrence rates between 26.5% and 33% at median of 2021 months without the use of preoperative radiotherapy (Table III) [7,14,20]. In the only other report where neoadjuvant radiotherapy was utilized in all patients, there was no local recurrence documented at a median follow up of 30 months [5]. The total of 10 patients treated with neoadjuvant radiotherapy reported in the literature

(including this study) have demonstrated excellent local control without any local recurrence reported at a median follow up of 30 and 37 months. There are several options available for the management of the resected IVC below the hepatic conuence; complete ligation, or reconstruction with or without an arteriovenous stula. IVC ligation is preferred in cases where the IVC is documented to be occluded preoperatively. However in our cases preoperative imaging did not reveal complete IVC occlusion and we therefore attempted reconstruction in all our patients. None of the patients developed severe edema or acute renal failure post-operatively. The use of harvested supercial femoral vein for reconstruction has several advantages: it is a large caliber vein, non-thrombogenic, and infection resistant [21]. Morbidity associated with the harvested deep vein is minimal with reported rates of chronic venous morbidity of less than 15% [21]. One of our patients required reoperation to control bleeding from the vein harvest site in the leg, and at a median follow up of 37 months only one patient was on anticoagulation. Two patients had patent IVCs on follow up imaging, one had a partial thrombosis and one had a complete occlusion of the IVC. None of the patients in the current study developed debilitating lower extremity edema related to IVC occlusion or deep vein harvest. Some authors have reported on the use of an arteriovenous stula to increase the patency rate but it is associated with the development of high output cardiac failure requiring stula ligation [8]. The advantages of IVC ligation are that it decreases operative time, graft infection, high output cardiac failure from creation of a stula and the need for long term anticoagulation. None of the complications listed occurred in this series and anticoagulation was only required for a short period of time in one of the cases. The disadvantages of IVC ligation are that it results in lower extremity edema which may be transitory [5], resection of the IVC above and including the conuence of the right renal vein mandates a right nephrectomy because of the lack of collaterals on the right and often results in a high rate of acute renal failure if autotransplantation is not performed [5,11]. The limitation of our study is that it is a small retrospective series, and denitive conclusions regarding neoadjuvant radiotherapy and reconstruction are difcult. However given that IVC leiomyosarcomas are rare with the largest series reported being of 22 patients it appears neoadjuvant radiotherapy may reduce local recurrence without an increase in morbidity, and the use of harvested vein graft appears to be safe and associated with acceptable outcomes compared to other described techniques for the management of the resected IVC. A multi-

TABLE III. Recent Case Series Principal investigator Hollenbeck et al. Ito et al. Cho et al. Daylami et al. Current study Refs. [12] [7] [18] [5] Year 2003 2007 2008 2010 n 21 20 9 6 4 RO (%) 33 40 78 67 100 Preoperative RTX 0a 7/20 0 6/6 4/4 Median follow up 24 months 41 months 47 months 30 months 37 months LR (%) 33 26.3 37.5 0 0 OR (%) 67 68 50 17 25 5-year OS 33% 62%b n/a n/a n/a

LR, local recurrence; OR, overall recurrence. a Five patients received either IORT or post-operative RT. b Overall survival of patients who underwent complete resections.

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institutional registry of patients treated with neoadjuvant radiotherapy and surgery would help clarify the oncological benets of this approach.

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Journal of Surgical Oncology DOI 10.1002/jso