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10.1245/s10434-006-9138-1
Annals of Surgical Oncology 14:568-576 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Preoperative Isolated Limb Infusion of Doxorubicin and External Irradiation for Limb-Threatening Soft Tissue Sarcomas

Mohamed A. F. Hegazy1, Sherif Z. Kotb1, Hanem Sakr2, Ebrahim El Dosoky3, Talal Amer4, Refaat A. F. Hegazi5 and Omar Farouk1

1 Department of Surgical Oncology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Nuclear Medicine and Radiotherapy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
4 Department of Diagnostic Radiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
5 School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Correspondence: Address correspondence and reprint requests to: Mohamed A. F. Hegazy; E-mail: mhegazy68{at}yahoo.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: At present, limb-sparing surgery is the most appropriate and acceptable treatment option for soft tissue sarcomas of the extremities. To increase the number of limb-sparing resections in the treatment of locally advanced soft tissue sarcomas of the extremities, preoperative radiotherapy and/or chemotherapy are often used. Isolated limb perfusion of cytostatic agents is an alternative effective option but technically complex. Isolated limb infusion, essentially a low-flow isolated limb perfusion without oxygenation via a percutaneous catheter, had been developed as a simple alternative.

Objective: The objective of this study was to achieve limb-sparing surgery in patients with locally advanced soft tissue sarcomas of the extremities that would otherwise have required an amputation or a functionally mutilating surgery by performing preoperative isolated limb infusion with doxorubicin and external beam irradiation to obtain local control and make limb-sparing surgery feasible.

Methods: A total of 40 patients with locally advanced soft tissue sarcomas of the extremities were evaluated between 2002 and 2005. Tumors were located in the lower limb in 28 patients (70%) and in the upper limb in 12 patients (30%). All these patients were felt to be unresectable and were referred because amputation was considered the only available treatment option. They underwent preoperative isolated limb infusion with doxorubicin (0.7 and 1.4 mg/kg for the upper and lower limbs, respectively). Preoperative external beam radiotherapy started within 3–7 days after isolated limb infusion was administered. The total dose was 35 Gy in ten fractions. After 3–7 weeks, surgery was performed aiming at limb preservation.

Results: Tumor response was seen in 85% of patients, rendering these large sarcomas resectable in most cases. The mean values of pretreatment tumor volume and post-treatment volume were 2797 cm3 and 1781 cm3, respectively, with a significant p value of 0.0001. Histologic response was seen in 80% of patients. At a median followup of 15 months (range = 5–35), limb salvage was achieved in 82.5%. Procedure-related complications were limited and easily managed.

Conclusion: Isolated limb infusion with doxorubicin is a simple and safe method of regional chemotherapy. The addition of preoperative external beam irradiation helped to increase the rate of limb salvage in patients with large and/or high-grade soft tissue sarcomas of the extremities.

Key Words: Isolated limb infusion • Soft tissue sarcoma • Doxorubicin • Limb salvage


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Soft tissue sarcomas (STS)make up approximately 1% of all malignant tumors.1 These tumors notoriously extend directly within muscle bundles, along nerve sheaths, and contiguous to fascial planes well beyond the confines of visible or palpable tumors. Not surprisingly, therefore, local recurrence rates after surgical excision are high, varying from 10% to 90%, depending on the extent of the surgical resection, the size of the tumor, its anatomical location, and the grade of differentiation.2 Independent of treatment, about 25–50% of patients who undergo limb-salvage surgery ultimately die of the disease.3

In the management of locally advanced extremity STS, limb salvage becomes all the more important in light of evidence that amputations do not improve survival rates in patients with large (>5 cm), deep-seated, or high-grade sarcomas.4

Preoperative therapies to improve limb-salvage rates have been propagated. Morton et al.5 first designed a preoperative treatment strategy using both intra-arterial chemotherapy plus accelerated fractionation radiotherapy as adjunctive treatment with the simultaneous purpose of achieving local disease control and limb-salvage surgery in patients who would otherwise require amputation or face a high risk of local recurrence. This was used successfully with curative intent in stage III or locally recurrent extremity sarcomas.6

The primary therapeutic goal of preoperative chemoradiation in patients with high-risk extremity STS is to maximize local control and minimize amputation rates. A secondary goal is to provide initial systemic treatment of potential micrometa-static disease; patients with localized high-risk STS have an approximately 50% chance of harboring subclinical micrometastasis at presentation.7

Isolated limb perfusion (ILP) is another strategy to deal with locally advanced STS. ILP is a regional cancer treatment that allows the administration of high doses of chemotherapeutic agents in a limb. This technique was developed in the late 1950s8 and was used in several cancer centers for the treatment of intransit melanoma metastasis of the limb rather than in limb sarcoma. Although it is effective, ILP involves complex and invasive operative procedures. A simplified procedure has been developed at the Sydney Melanoma Unit and is called isolated limb infusion (ILI) that has been shown to give overall response rates comparable to those observed after conventional ILP.9

In this study we applied ILI plus external irradiation preoperatively to cases with locally advanced extremity STS. Our aim was to identify the feasibility of applying ILI, to assess the procedure-related complications, and to assess its advantage (if any) on the disease-free and overall survival of these patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Between July 2002 and June 2005, a total of 40 patients with high-grade or large STS of the extremities were treated. All of these patients were considered unresectable and were referred because amputation was considered the only available treatment option. Patient characteristics are summarized in Table 1Go.


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  		TABLE 1. Characteristics of 40 patients with locally advanced extremity soft tissue sarcomas
 
Unresectability Criteria
All the cases included in the study were considered either unresectable or could be resected with a major functional compromise because they were affected by high-risk extremity STS. The unresectability criteria include multifocal primary tumors in the limb, fixation to the neurovascular bundle and/or the bone, recurrence in a previously irradiated area, location in or near a joint or large tumor necessitating an extensive resection that would severely compromise the limb function.

Preoperative Regional Chemotherapy
All patients underwent preoperative isolated limb infusion with doxorubicin. The procedure of ILI was performed in the angiography room. No general anesthesia was required; the patient was sedated by intravenous (IV) midazolam 0.01 mg/kg and the local anesthetic xylocaine was applied on the groin at the puncture site of the catheter. Heparin (3 mg/kg) was given to obtain full systemic heparinization. The technical details of ILI procedures were as described by Thompson et al.9,10 In brief, standard radiologic catheters were inserted percutaneously into the axial artery and vein of the disease-bearing limb via the contralateral groin. The catheter tips were positioned at the level of the major feeding vessels of the tumor. Then the contrast medium (urovidio) was injected through the catheter to evaluate the vasculature of the tumor region and to obtain angiographic run, determining the feeding vessel of the tumor. When it was confirmed that the position of the angiographic catheter was satisfactory, a pneumatic tourniquet was inflated around the root of the limb to be treated and the cytotoxic agent (doxorubicin 0.7 and 1.4 mg/kg for the upper and the lower limbs, respectively) was infused into the isolated limb via the arterial catheter. For the duration of the ILI procedures (15–25 min), the infusate was then continually circulated by repeated aspiration from the venous catheter and reinjection into the arterial catheter by using a syringe attached to a three-way tap in the circuit. After 15–25 min the limb was flushed with 1 L of Hartman’s solution via the arterial catheter. The limb tourniquet was then deflated to restore normal limb circulation and the catheters were removed.

Preoperative Irradiation
Preoperative external beam radiotherapy started within 3–7 days after ILI was administered. The target volume included all detectable tumors as determined by clinical examination and magnetic resonance imaging (MRI). The total dose was 35 Gy applied in ten fractions of 350 cGy per day over 12–14 days.

Assessment of Tumor Response
Clinical response was assessed as follows: complete response (CR: complete disappearance of all measurable or evaluable tumor for a minimum of 4 weeks), partial response (PR, greater than 50% reduction of the tumor volume lasting at least 4 weeks), minor response (MR, reduction of the tumor volume by less than 50% for at least 4 weeks), stable disease (SD, less than 25% increase in the tumor volume for at least 4 weeks), and progressive disease (PD, an increase of greater than or equal to 25% of the tumor volume and/or occurrence of new lesion).

Extensive histopathologic examination of the resected specimen was performed. The histologic response was assessed by comparing the degree of tumor necrosis before ILI as obtained from core biopsies performed in newly diagnosed cases or from previous resection specimens in recurrent cases. It was classified as follows: good response (greater than 90% tumour necrosis), fair response (60%–90% tumor necrosis), and poor response (less than 60% tumour necrosis).

Surgical Treatment
Surgery was performed within 3–7 weeks after completion of preoperative external beam radiotherapy. Usually this period allowed for enough shrinkage of the tumor and allowed the soft tissues to recover from the inflammatory response to radiotherapy.

The operation was a wide local excision with the goal of obtaining tumor-free histologic margins but sparing major neurovascular structures. A wide excision included a 1-cm minimum margin of normal-appearing tissue around the specimen with a muscle or fascial barrier between the tumor and the surgical margin. A marginal resection was performed for patients in whom at least one resection margin had to be compromised to spare a major artery, nerve, or bone and preserve limb function. Multiple frozen section biopsies from the wound were obtained to ensure negative margins. After excision, vascularized muscle flaps were used whenever possible to cover any major vessel, nerve, or bone.

Postoperative Therapy
Postoperative adjuvant chemotherapy was given for patients with high-grade sarcomas and those at high risk for distant micrometastasis. We administered VAC protocol: vincristine [1.4 mg/m2 IV bolus, maximal dose 2mg, day 1(+5)], adriamycin [50 mg/m2 IV short infusion, day 21], and cyclophosphamide [750 mg/m2 IV bolus, day 1–5], repeated every 4 weeks for 6 cycles.

Assessment for Complications
Procedure-related complications were graded according to Weiberdink et al.4: 1 = no toxicity; 2 = redness and slight edema; 3 = considerable erythema or edema with slight blistering, slightly disturbed mobility possible; 4 = extensive epidermolysis or obvious damage to the deep tissues, causing definite functional disturbances; threatening or manifest compartmental syndrome; and 5 = reaction requiring amputation.11

Postoperative wound complications were defined using the definitions developed and used in the Canadian Sarcoma Group SR2 trial of pre- versus postoperative radiation for extremity STS.12 Major wound complications were defined as those that required (1) secondary operation under general or local anesthesia for wound repair (debridement, preoperative drainage, and secondary wound closure), (2) an invasive procedure not requiring general or regional anesthesia (mainly aspiration of seroma), (3) readmission for wound care as IV antibiotic therapy, or (4) persistent deep packing of the wound for 120 days or longer.

Statistical Methods
Data were analyzed using SPSS (MicroSoft Windows release 11; SPSS Inc., Chicago, IL). Quantitative data were tested for normality by the Kolmogrov-Smirnov test. Normally distributed data were presented as mean and standard deviation. Paired t test was used to compare the results before and after therapy. Nonparametric data were presented as minimum – maximum and median. Survival was compared using Kaplan-Meier method. Survival data were calculated from the start of treatment.

The protocol was approved by all local ethical committees at the Mansoura University. Informed consent was obtained from all patients before treatment.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Tumor Volume Response
Thirty-four patients (85%) showed a response to preoperative intra-arterial injection of chemotherapy and external radiotherapy. Twelve of the 34 patients showed partial response (Fig. 1Go), and 22 showed minimal response (Fig. 2Go). The mean values of pre-treatment tumor volume and post-treatment were 2797 ± 915 cm3 and 1781 ± 593 cm3, respectively (P = 0.0001). All patients showed an increase in the extent of necrosis and extensive cystic degeneration of their tumors as detected in MRI (Figs. 1Go and 2Go).


Figure 1
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  		FIG. 1. MRI of a case of liposarcoma in the upper posterior aspect of the leg showing a partial tumor volume response (53.1%). Increased extent of necrosis (N) and cystic degeneration is noted in the postoperative film (left).

 

Figure 2
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  		FIG. 2. MRI of a case of pleomorphic liposarcoma in the posteromedial aspect of left thigh showing a minimal tumor volume response (18%). Left film shows the post-treatment increase in the extent of necrosis (N) and cystic degeneration (C).

 
Histopathologic Response
Histopathologic response was detected by assessment of the degree of tumor necrosis. Thirty-two patients (80%) showed pathologic response; 15 of those patients showed good response (Fig. 3Go) and 17 patients showed a fair response (Fig. 4Go). The remaining 8 patients showed poor response.


Figure 3
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  		FIG. 3. Pretreatment histopathologic pattern of pleomorphic liposarcoma (right). Post-treatment figure (left) shows good histopathologic response. N, necrosis; T, tumor cells.

 

Figure 4
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  		FIG. 4. Pretreatment histopathologic pattern of extraskeletal osteosarcoma (right). Post-treatment figure (left) shows fair histopathologic response. N, necrosis; T, tumor cells.

 
Procedure-Related Complications
Local morbidity to ILI developed in 12 patients (30%). These were graded using the scale proposed by Wieberdink et al.11 Eight cases experienced grade 2 complications (slight edema and/or erythema) and four cases experienced grade 3 complications with only one case having slight motility impairment. There was no grade 4 or 5 toxicity.

Limb Salvage and Surgical Complications
Tumor response was seen in 34 cases (85%), rendering most of these large sarcomas resectable. All these patients had a functional extremity postoperatively, although some (4 cases) had motor weakness because of sacrificed nerves. One patient subsequently required amputation for an overall limb salvage rate of 82.5%. This patient had grade III malignant fibrous histiocytoma in the medial aspect of the right thigh. He showed PR (partial response) to neoadjuvant ILI and RT and wide local excision was done. After five months, he developed an extensive local recurrence that required hip disarticulation. Seven patients show no response: Amputation was performed in three cases, two cases refused amputation and were referred for EBRT (external beam radiotherapy) and/or systemic chemotherapy, and the remaining two cases showed distant metastasis.

Major wound complications were noticed in three patients (7.5%). Two of these patients experienced wound complications requiring readmission. One of them underwent reoperation for wound debridement and secondary closure and the other one was admitted for IV antibiotic therapy because of a persistent wound infection. The third patient underwent repeated aspiration for seroma.

Local Recurrence
After a median followup time of 15 months (range = 5–35), four patients (13.3%) had local recurrence. One of them underwent amputation, two underwent marginal resection and reirradiation, and one had local excision and chemotherapy for distant metastasis (Fig. 5Go).


Figure 5
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  		FIG. 5. Local recurrence-free survival following ILI with doxoru-bicin and external beam irradiation of soft tissue sarcoma (Kaplan-Meier estimates).

 
Distant Metastasis
In three patients (7.5%), synchronous metastasis was present at the time of ILI. Limb salvage was achieved in all of them. Two of them died (median = 8 months). At a median followup of 15 months, distant metastasis appeared in 17 of 37 (46%) remaining patients (after excluding the 3 patients who were initially metastatic), 9 of these 17 patients have died (9/17 = 53%) (Fig. 6Go).


Figure 6
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  		FIG. 6. Metastasis-free survival following ILI with doxorubicin and external beam irradiation of soft tissue sarcoma (Kaplan-Meier estimates).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Over the past 30 years, limb-sparing surgery has almost completely replaced amputation for sarcomas of the extremities. Two factors have greatly contributed to this development: improvement in locoregional adjuvant therapies and an improved understanding of the natural history of these tumors. Today small (<5 cm) and superficial sarcomas require simple resection with safety margins, irrespective of their grade of malignancy, whereas larger tumors often require multimodality treatment especially if they are high grade and deep seated.13

High-grade soft tissue sarcomas that undergo local treatment by surgery alone have a local recurrence rate as high as 70%–90%. Surgical resection with wide margins results in a lower recurrence rate at the cost of removing a wide margin of normal tissue which is often not feasible depending on the location of the tumor.14 The addition of moderated doses of external beam irradiation (50 Gy) allows for more conservative surgery with an equivalent rate of local tumor control and has become the standard of care.15 This was verified by the studies of Rosenberg et al.16 and Pisters et al.17 who showed equivalent disease-free survival in patients treated by a wide en bloc resection followed by external beam irradiation compared with those undergoing amputation. It should be pointed out that the achievement of local control appears not to correlate with a patient’s long-term survival and likelihood of developing metastasis.18 In this regard neoadjuvant chemotherapy has been studied. Neo-adjuvant chemoradiotherapy has some theoretical advantages. First, a substantial number of patients may not be able to get postoperative chemotherapy or radiotherapy because of delayed wound healing, possibly resulting in recurrence before definitive local therapy.19 It may also allow for smaller and less morbid operations in some instances. Preoperative chemotherapy could prevent progression of micrometastases. On the other hand, its disadvantages include delayed time to local control if the preoperative treatment is ineffective and poor wound healing.20

One way to increase the efficacy of neoadjuvant chemotherapy is ILP. ILP has the theoretical benefit over surgical resection in that it allows one to treat an entire area at the risk of recurrence, and it differs from traditional chemotherapy in that doses ten times higher than the allowed systemic dose can be used.21 Recently, ILI appeared to be a simpler alternative to ILP.22 ILI differs from ILP in that arterial and venous catheters are inserted percutaneously without surgery and a bypass circuit is not involved.10 Chemotherapy is given for a shorter period to an extremity that is both hypoxic and acidotic. Response rates to regional chemotherapy using ILI are comparable to those of ILP.9

In STS, melphalan, the standard drug for ILP of melanoma, has been studied most extensively, although other agents (doxorubicin, cisplatin) have also been applied.23,24

As a single agent, doxorubicin is probably the most active drug against STS.25 However, some authors have expressed concern that doxorubicin administered through ILI might cause more local toxicity than L-PAM.26 In a phase I study, the maximum tolerated dose of doxorubicin was found to be 0.7 and 1.4 mg/kg for the upper and lower limbs, respectively.27 Furthermore, a study was performed to evaluate the toxicity of doxorubicin and L-PAM in muscle tissue at the microscopic level.28 While the microscopic features significantly differed before and after ILI with both drugs, no difference was found between muscle biopsies from patients treated with L-PAM and those treated with doxorubicin.

Preoperative intra-arterial chemotherapy usually based on doxorubicin can result in a sixfold increase in drug concentration perfusing the tumor.29 Overall response rates and limb-sparing surgery rates of 47% and 80%–90%, respectively, were reported.30,31 Some authors combine this approach with preoperative EBRT. Results of both local disease control rate (85%–95%) and limb-sparing surgery rate (81%–97%) seem quite satisfactory.32,33 Nevertheless, this combination treatment is associated with a high incidence of complications (26%–60%) and has not been evaluated in limb-threatening STS but with high-grade tumors considered at risk of recurrence.34

To our knowledge this is the first report of a study evaluating preoperative isolated limb infusion of doxorubicin combined with neoadjuvant radiotherapy aimed at limb-sparing surgery in limb-threatening STS. In our series an overall limb-salvage rate of 82.5% could be achieved at a median followup of 15 months. Considering that this group of patients has large (mean pretreatment tumor volume = 2797 cm3), multiple, or fixed tumors, these results show the efficacy of such an approach.

Contrary to the previous concerns regarding the safety of the protocol, our experience shows that preoperative ILI and external beam irradiation is safe and associated with only mild to moderate regional and systemic toxicity. The 12 patients who experienced local morbidity were all grade II or III according to Wieberdink criteria. No case of grade IV or V toxicity was encountered. The impact of the procedure on wound healing is minimal, with only three patients (7.5%) experiencing mild postoperative wound complications.

The local recurrence rate of 13.3% is low considering the large tumor size, the percentage of recurrent tumors treated, and the conservative type of surgery used on these patients. In a study by Rossi et al.,23 local recurrence occurred in 4 of 19 patients (21%) who had hyperthermic antiblastic perfusion with doxorubicin and surgery, with or without postoperative EBRT. The addition of preoperative EBRT in our cases could be responsible for the lower recurrence rate in our series.

Our results are comparable to the recent trials of tumor necrosis factor (TNF)-based isolated limb perfusion. Rossi et al.27 performed ILP with TNF and doxorubicin and achieved an 85% limb-sparing surgery rate and a 9% local recurrence rate. This regimen was associated with higher local toxicity, 15% of which were grade IV according to Wieberdink criteria. Lejeune et al.35 reported their results with rh TNF and L-PAM isolated limb infusion achieving an 86% limb-sparing surgery rate, a 45% local recurrence rate, and no severe local complications. In a comparable group of patients with particularly unfavorable characteristics, like those included in our study, Noorda et al.36 and Grunhagen et al.37 reported somewhat less favorable results. The Amsterdam group in 200336 reported their experience in 49 patients: the limb-salvage rate was 58%. The Rotterdam study of patients with recurrent sarcomas after surgery and radiotherapy included 24 patients and reported a response rate of 74% and a limb-salvage surgery rate in 67%.37


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
The simplified ILI methodology provides us with a novel therapy to obtain local control and avoid amputation in cases of limb threatening soft tissue sarcoma. The addition of preoperative radiotherapy seems to add significantly to improving the local control rates without any significant increase in local or systemic morbidity. The superiority of one protocol over the other in ILI for extremity sarcomas warrants further randomized controlled trials.

Received for publication June 17, 2006. Accepted for publication June 26, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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Ann. Surg. Oncol., November 1, 2008; 15(11): 3003 - 3013.
[Abstract] [Full Text] [PDF]

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M. D. Moncrieff, H. M. Kroon, P. C. Kam, P. D. Stalley, R. A. Scolyer, and J. F. Thompson
Isolated Limb Infusion for Advanced Soft Tissue Sarcoma of the Extremity
Ann. Surg. Oncol., October 1, 2008; 15(10): 2749 - 2756.
[Abstract] [Full Text] [PDF]

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