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10.1245/ASO.2005.03.064
Annals of Surgical Oncology 12:646-653 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Preoperative Chemoradiotherapy (Modified Eilber Protocol) Provides Maximum Local Control and Minimal Morbidity in Patients With Soft Tissue Sarcoma

Lloyd A. Mack, MD1, Phil J. Crowe, MD2, Jia Lin Yang, MEd, PhD2, Norman S. Schachar, MD3, Don G. Morris, MD, PhD1, Elizabeth C. Kurien, MD1, Claire L. F. Temple, MD3, Robert L. Lindsay, MD3, Enzio Magi, MD3, William G. DeHaas, MD3 and Walley J. Temple, MD, FRCSC, FACS1

1 Division of Surgical Oncology, University of Calgary, Tom Baker Cancer Centre, 1331 29th Street N.W., Calgary, Alberta, Canada, T2N 4N2
2 Department of Surgery, University of New South Wales, Prince of Wales Hospital, High Street, Randwick, New South Wales, Australia 2031
3 Department of Surgery, University of Calgary, Foothills Medical Centre, 1403 29th Street, N. W., Calgary, Alberta, Canada, T2N 2T9

Correspondence: Address correspondence and reprint requests to: Walley J. Temple, MD, FRCSC, FACS; E-mail: walleyte{at}cancerboard.ab.ca.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Local recurrence rates of 15% to 30% after treatment of soft tissue sarcoma (STS) are still common but unacceptable. Our hypothesis was that a refined neoadjuvant chemotherapy and radiation protocol (modified Eilber protocol) improves local control rates while minimizing major morbidity.

Methods: Consecutive patients with STS deep to the fascia of the extremity or trunk during 1984 to 1996 were treated with 3 days of doxorubicin (30 mg/day) and sequential radiation (300 cGy/day for 10 days). Wide excision with limb preservation was performed 4 to 8 weeks after radiation completion. Treatment complications, margins, local recurrence, and survival were prospectively documented.

Results: Of 75 patients, 66% had tumors >5 cm, and 71% were grade 2/3. In eight patients, negative margins were not achieved, and four of these had amputation (95% limb salvage). Three of the remaining four had local recurrence with a 5- and 7-year actuarial local control rate of 50% and 25%, respectively. In contrast, of the 67 patients with negative margins, a local control rate of 97% at 5 years and 94% at 7 years and an overall survival of 63% were achieved. Although margin (P = .001) and stage (P = .035) were correlated, these were not significant on multivariate Cox regression analysis. Risk factors for death included tumor stage (hazard ratio, 1.54; P = .001) and tumor grade (hazard ratio, 1.4; P = .02). Three patients (4%) required reoperation for tissue loss, and eight patients (10.6%) developed minor wound complications.

Conclusions: This modified Eilber protocol seems to maximize local control and minimize major wound complications for extremity/truncal STS.

Key Words: Soft tissue sarcoma • Limb-sparing surgery • Combined-modality therapy • Local control


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Limb-sparing surgery is the current standard of care for patients with extremity soft tissue sarcoma (STS).1,2 However, local control continues to be a challenge. Surgery followed by adjuvant radiotherapy is the most common treatment approach. Despite such multimodality therapy, local recurrence may occur in 15% to 30% of cases even at centers with significant expertise in treating STS.3–8

A standardized neoadjuvant chemoradiation protocol, a modification of a neoadjuvant protocol presented by Eilber et al.,1 has been used at our center for nearly two decades.9 All consecutive patients with deep STS have been treated via this standardized protocol. Our center has been referred >90% of patients with a diagnosis of sarcoma in southern Alberta, thus suggesting a population-based treatment modality. Our hypothesis is that appropriately dosed combination preoperative chemotherapy and radiotherapy followed by wide local excision will decrease local recurrence rates of STS without significant increases in wound complications. This article augments an original publication of results in 42 patients: a total of 75 patients with a median follow-up of 6.75 years have been accrued.9


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All patients who presented with STS between 1984 and 1996 were entered into a prospective sarcoma database. Pathologic diagnosis was established by open biopsy or computed tomographic – guided core biopsy at our center or by excision at another center in the case of inadequately excised or recurrent tumors. All pathology was reviewed and confirmed at the Tom Baker Cancer Centre before consideration for inclusion in the trial. All patients with STS of the extremity or trunk that was deep to muscular fascia, including recurrent tumors initially treated elsewhere, were eligible. Patients were staged with chest radiographs at a minimum, although computed tomographic scan of the chest was more commonly used later in the trial. Patients with metastatic disease were reviewed on a case-by-case basis at multidisciplinary sarcoma rounds and were eligible if they had potentially resectable lung metastases. Patients were not eligible if they had extensive metastatic disease or if the primary tumor had obvious major neurological compromise (e.g., sciatic nerve) or invaded bone that was not amenable to reconstruction.

After informed consent, all eligible patients received a protocol of 3 days of preoperative Adriamycin (30 mg/day) and sequential radiotherapy of 3000 cGy (300 cGy per day for 10 days), as previously described.9 Distal extremity tumors were generally treated with intra-arterial chemotherapy, whereas more proximally placed lesions were treated intravenously via a central line. Patients with sarcomas of the distal upper limb empirically received <90 mg of doxorubicin (60 – 75 mg), as did two adolescent patients (30 – 75 mg). Wide surgical excision was then performed 4 to 8 weeks after the completion of radiotherapy. Surgical resection was performed through grossly normal tissue planes, and the adventitia of the artery/vein and epineurium was removed if the tumor abutted a neurovascular structure. Patients with involved margins after excision were recommended to have re-excision or amputation to achieve clear margins. Margins of ≥1 cm were considered wide, <1 cm was considered marginal, and tumor at the resected specimen edge was considered involved or positive. Tumor grade was divided into low, moderate, or high.4,10 Staging was via a modified American Joint Committee on Cancer classification.11

All patients were followed up at a multidisciplinary sarcoma clinic until the end of follow-up or death, and all treatment details and outcomes, including local, regional, and distant recurrences, were recorded prospectively. Patients with high-grade tumors were followed up at least every 4 months until 2 years and then annually. Patients with low- or moderate-grade tumors were followed up at least every 6 months until 2 years and then annually. Major wound complications were defined as those requiring reoperation for tissue loss or necrosis and were recorded prospectively. Minor wound complications included seromas, hematomas, cellulitis, or minor wound infections requiring debridement, packing, or both and were determined by retrospective database, clinic, and hospital chart review.

Data were analyzed with SPSS statistical software (SPSS Inc., Chicago, IL). Associations between variables were studied by using nonparametric Kruskal-Wallis or Mann-Whitney U-tests as appropriate. Survival analysis was performed by using the method of Kaplan and Meier and log-rank tests, and prognostic factors were assessed with the Cox proportional hazards model (Cox regression) with the forward likelihood ratio statistical method.12,13 Univariate and multivariate analysis was used to determine the significance and independence of prognostic factors for the risk of local recurrence, distant metastases, and overall survival. For variables found to have prognostic value by the Cox regression analysis, relative risks with confidence intervals (CIs) were calculated.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient and Tumor Characteristics
Seventy-five patients were consecutively treated and have been followed up for a median of 6.75 years (95% CI, 5.67 – 7.83 years) or until death. The median age of the study population at presentation was 50 years (95% CI, 13 – 84 years). There were similar numbers of cases for each sex. Ten (13%) of 75 patients had recurrent tumors initially treated at other centers. Tumor locations and histologies are listed in (Table 1Go). Fifty-one percent of cases were of the proximal lower limb, and 23% were of the distal lower limb. Histologies included liposarcoma (22.7%), malignant fibrous histiocytoma (21.3%), leiomyosarcoma (16%), synovial cell sarcoma (16%), and others (24%).


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  		TABLE 1. Tumor location and histology
 
Tumor grade, size, and stage are listed in Table 2Go. Tumors were moderate to high grade in approximately 70% of cases. Two thirds of tumors were >5 cm in greatest dimension. All sarcomas were deep to the muscular fascia. Eighty percent of cases were stage IIB or higher. Four patients had stage IV disease treated for local palliation or when resection of pulmonary metastases was considered.


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  		TABLE 2. Tumor grade, size, and stage
 
Morbidity
There were no in-hospital or 30-day mortalities. Plastic surgery reconstruction occurred where necessary, mainly in patients with significant dead space after tissue resection. Three patients (4%) required reoperation for tissue loss of a myocutaneous flap, skin graft, or wound that had been closed primarily. All of these occurred in the immediate postoperative period before patient discharge. Eight patients (10.7%) had minor wound complications, including seroma, infection, or minor wound breakdown amenable to local wound care, antibiotics, or drainage. The overall wound complication rate (major and minor) was 15%. Four patients had complications directly attributable to chemotherapy in the form of tissue redness from streaming (n = 1), migration of the intra-arterial catheter into the vertebral artery with neurological signs (n = 1), or thrombi in the femoral artery due to perceived inadequate heparinization (n = 2). All neurological symptoms and signs resolved with removal of the migrated catheter, and arterial flow was re-established via thrombectomy in the two patients with femoral artery thrombosis. All four patients who developed intra-arterial chemotherapy complications had their remaining dose of Adriamycin delivered intravenously. There were no significant complications with intravenous Adriamycin. There was no long-term complication of wound breakdown, bone fracture, or distal neurovascular toxicity, and there were no radiation-induced cancers. Lymphedema rates were not routinely measured. A proportion of patients did have bronzing or thickening of the skin, but this was not routinely measured and not believed to be clinically significant.

Margin, Recurrence, and Survival
After wide local resection, 45% of patients had a >1-cm margin, and 44% had a marginal (<1 cm) resection to preserve vital neurovascular structures. Eight patients (of 75) had positive margins after initial resection and were recommended to have amputation or re-resection for positive margins. Four went on to have amputation (95% limb salvage) because re-resection for clear margins was not possible without resecting important neurological structures (i.e., the sciatic nerve). Three of the remaining four had local recurrence with an actuarial local control rate of 50% at 5 years and 25% at 7 years; one had re-resection and is free of disease, and two died with local and distant disease (Fig. 1Go). The one patient without local recurrence died without evidence of disease.


Figure 1
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  		FIG. 1. Local relapse – free probability.

 
Of the 67 patients with negative margins, 4 had local recurrences by 7 years, for an actuarial local control rate of 97% at 5 years and 94% at 7 years (Fig. 1Go). Two of the patients with local recurrence had further wide local excision and maintained local control. One elderly patient died with local disease, and one died with concurrent metastatic and local recurrence. The overall 5-year survival was 63% ± .05% (cumulative survival ± SE; Fig. 2Go). Although margin and stage were significantly associated with local recurrence (Kruskal-Wallis for multiple groups, P = .001 and .035, respectively; log-rank test, all P < .001), these were not significant on multivariate Cox regression analysis. Predictors of distant metastasis after Cox multivariate regression analysis included tumor stage (hazard ratio [HR], 1.4; P = .041; 95% CI, 1.1 – 1.8) and tumor grade (HR, 1.3; P = .040; 95% CI, 1.01 – 1.74). Similarly, risk factors for death included increased stage (HR, 1.54; P = .001; 95% CI, 1.2–2.0) and tumor grade (HR, 1.4; P = .02; 95% CI, 1.1 – 1.9).


Figure 2
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  		FIG. 2. Overall survival.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This prospective series demonstrates enhanced local control compared with most series. Furthermore, improved local control has been combined with decreased major wound morbidity, especially when compared with standard preoperative radiotherapy.14–16 Combined neoadjuvant chemoradiotherapy with limb salvage surgery is an excellent option for treating patients with deep STS of the extremity or trunk.

The quest for improved local control began after early critical trials demonstrated no adverse difference in survival after limb-sparing surgery.1,2 Although Rosenberg et al.2 reported no difference in overall survival in a randomized trial comparing amputation with limb-sparing surgery, 4 (15%) of 27 patients undergoing limb-sparing surgery had a local recurrence. Local recurrence remains a concern because of increased morbidity, the increased likelihood of amputation, and a possible (yet controversial) relationship to survival.17

Eilber et al.1 introduced a protocol of neoadjuvant therapy that consisted of intra-arterial Adriamycin, sequential preoperative radiation (350 cGy/day for 10 days), and then limb-sparing surgery. They reported an impressive 96% limb salvage rate and 4% local recurrence rate. Unfortunately, a reported 35% wound complication rate and a 23% reoperation rate precluded widespread adoption of this protocol. Therefore, the current protocol, which includes a reduced preoperative radiation dose, was intended to improve the rate of significant wound complications yet maintain a high level of local control.9 A local control rate of 94% in this series combined with a low 4% major wound complication rate represents a considerable advance in the treatment of STS.

Most specialized cancer centers report local recurrence rates of 15% to 30% after treatment with surgery alone or surgery and preoperative or postoperative radiotherapy.3–8 A series from the Memorial Sloan-Kettering Cancer Center notes a 17% recurrence rate among 1041 patients with localized STS of the extremity at a median follow-up time of 3.95 years.3 Eighty-seven percent of patients had a limb-sparing procedure. Analysis of 1225 patients with localized STS at the M. D. Anderson Cancer Center determined a 20% 10-year local recurrence rate.8 Patients had limb-conservation surgery plus preoperative (23%) or postoperative (77%) adjuvant radiotherapy. Coindre et al.4 noted an overall local recurrence rate of 29% among 546 patients with locally controlled STS. Predictors of local recurrence include age >50 years, presentation with locally recurrent disease, microscopically positive margins, tumor size >10 cm, high-grade pathology, tumors deep to the muscular fascia, lack of radiotherapy, primary tumor location in the head and neck or deep trunk, and histopathologic subtypes including malignant fibrous histiocytoma, epithelioid sarcoma, and malignant peripheral nerve tumor.3,4,8 These series report either local control for macroscopically negative resections4 or overall local control rates for microscopically negative and positive margins.3,8 However, positive microscopic margins also had postoperative radiotherapy in most cases. In contrast, further surgery was recommended for positive margins in this trial. We separated control rates for positive and negative margins because some patients with positive margins had amputation or refused further surgery. Following patients with positive margins and no further therapy is not a true test of the protocol because they have residual disease at the outset. Similarly, following for local control after amputation would not be a test of the protocol intended for limb-sparing surgery. Of note, if we currently had a patient with positive margins after the protocol and surgery, re-excision would be recommended if possible when function was maintained or additional postoperative radiation would be recommended. If patients refused further radiation, we would observe expectantly rather than recommend amputation, because a local recurrence could then be dealt with when or if it occurred.

Eilber et al.17 reported an overall local recurrence rate of 12% at 5 years among 756 patients. A subgroup of 498 patients treated with preoperative neoadjuvant chemoradiation had a local recurrence rate of 11% at 5 years and 15% at 10 years.18 Failure to receive neoadjuvant therapy was the only factor associated on multivariate analysis with an increased risk of local recurrence in patients who presented with locally recurrent disease.17 An earlier study by the same group of neoadjuvant Adriamycin and 35 Gy of radiation noted a 4% local recurrence rate.1 Decreasing the radiation dose to 17.5 Gy in an attempt to avoid wound complications led to a local recurrence rate of 20% among 95 patients with high-grade sarcoma.19 A dose of 28 cGy has been used in subsequent protocols at the University of California – Los Angeles, with improved local control. A notable exception with a very low local recurrence rate after limb-sparing surgery does exist. A randomized study of 141 patients reported a local recurrence rate of 1.5% with surgery plus postoperative radiotherapy, versus 24% with surgery alone.7

Some investigators have noted a low local recurrence rate with surgery alone in well-selected patients.6,20–23 In general, surgical resection without additional therapy is considered in patients with good-prognostic sarcomas: superficial or subcutaneous tumors or deep tumors that are low grade, <5 cm, and clear of neurovascular structures.6,20–23 These tumors represent a good-prognosis, biologically different subgroup that is not directly comparable with the tumors in this study. The current protocol is applied only to STS occurring deep to the muscular fascia. Furthermore, two thirds of tumors were >5 cm, 44% of cases had marginal resections to preserve neurovascular structures, 13% were recurrent, and 70% were moderate or high grade. Although surgery alone may be justified for low-risk STS superficial to the muscular fascia, the authors believe that radiation, at a minimum, is required for deep STS.

It is our impression that the combination of preoperative radiotherapy and chemotherapy for deep STS makes the most biological sense. Purported advantages of preoperative radiation include a smaller total treatment volume, a well-oxygenated tumor requiring a decreased overall radiation dosage, the potential for preoperative tumor shrinkage or downstaging, and an increased ability to obtain histologically negative margins.14,17,19,20,24,25 Pollack et al.14 noted a better local control rate of 88% at 10 years with preoperative radiation for primary gross disease, as compared with 67% with postoperative radiation (P = .01). A retrospective study by Suit et al.15 noted improved local control for patients with large (>15 cm), proximally placed STS with the use of preoperative versus postoperative radiotherapy. The only randomized trial of preoperative versus postoperative radiotherapy for STS has not yet reported on local recurrence rates.16,26

The addition of preoperative Adriamycin, a radiosensitizing agent when combined with radiotherapy, facilitates a less radical surgical resection secondary to treatment-induced cytoreduction or sterilization of margins.18,27 A review of 496 patients treated with neoadjuvant chemoradiation showed only 16 patients (3%) with positive margins after operation.18 A randomized trial suggests that intravenous Adriamycin is as effective as intra-arterial Adriamycin for prevention of local recurrence.19,28 Our center currently uses intravenous Adriamycin exclusively.

A 5-year overall survival rate of 63% with the current protocol is no different from rates in the current literature. Similarly, improvements in overall survival have not been seen even with significant improvements in local control.2,7,29,30 However, a time-dependent multivariate analysis of 753 patients demonstrated a significantly worse survival in those with local recurrence (HR, 2.89; 95% CI, 2.02 – 4.11), thus suggesting that local recurrence is a predictor of biologically aggressive tumors.17 Furthermore, local recurrence was associated with considerable morbidity; it led to loss of function and amputation in nearly 40% of patients.17 Although neoadjuvant Adriamycin, at the dosage used in the current protocol, is unlikely to have any affect on overall survival, an optimal local control rate of 94% and major wound complications in only 4% is the ideal starting point for further trials of adjuvant chemotherapy.

A significant concern regarding preoperative radiotherapy is an increase in both the overall and major wound complication rates. Pollack et al.14 noted 25% and 6% wound complication rates when 50 Gy of preoperative radiation was used, compared with 64 Gy of postoperative radiotherapy, respectively. Suit et al.15 commented on an increased frequency of wound complications that led them to decrease preoperative radiation doses and recommend the consideration of myocutaneous flaps to improve wound healing. A randomized trial designed to address this issue noted a 35% risk of major wound complications with preoperative radiation (50 Gy) versus a 17% risk with postoperative radiotherapy (50 Gy plus a 16- to 20-Gy tumor bed boost).16 Fourteen of 88 patients in the neoadjuvant arm had additional postoperative radiation (16 – 20 Gy) because of positive resection margins. Major wound complications were defined as those that necessitated a secondary operation or invasive wound management, including readmission for wound care or persistent deep packing for 120 days or longer. Despite obvious differences in major wound complication rates, there was no significant difference in function at 1 year after operation between the two treatment arms.26 Preliminary assessment of upper limb function (12 patients) by using the Musculoskeletal Tumor Society score noted a median score of 28 of 30 (mean, 26.7; range, 17 – 30), or 93%; this confirmed good to excellent function in the current patient group, and formal testing of lower limb sarcoma patients is planned. A 4% reoperation rate compares favorably with the 15% reoperation rate in the preoperative radiation arm of the National Cancer Institute of Canada randomized trial.16 However, overall wound complication rates are not comparable because the National Cancer Institute of Canada data were all prospectively collected, and only major wound complication data were prospectively obtained in the current trial; minor wound complication data were retrospectively obtained. It is our impression that a lower overall dose of radiation, 30 Gy compared with 50 Gy in most trials, likely decreases the risk of impaired wound healing, especially if operation is delayed at least 4 weeks. The addition of synergistic Adriamycin maintains an optimal local control rate despite a decreased radiation dosage.

Plastic surgical reconstruction is being used with increasing frequency at our center. It is our opinion that specialized plastic surgical techniques including vascularized myocutaneous flaps have contributed to a decrease in wound complications, although this was not demonstrated statistically in the study by O’Sullivan et al.16 In groin sarcoma patients treated with the neoadjuvant protocol, no major wound complications were observed. This was largely attributable to rectus myocutaneous flap reconstruction.31 The modified Eilber protocol, prophylactic antibiotics, appropriate tissue handling, judicious use of drains, and expert wound closure, including vascularized myocutaneous flaps, all likely contribute to a lower major wound complication rate.

The development of a multidisciplinary team is critical to the success of this neoadjuvant protocol. Although traditionally the group includes surgical, radiation, and medical oncologists, the role of the reconstructive microsurgeon is emerging, particularly in view of the decrease in complication rates seen with the use of flaps in wound closure. The decision-making process regarding the feasibility of limb salvage not only is oncologically determined, but also is predicated on whether the reconstructive surgeon can achieve a healed wound and reconstitute a functional extremity. The oncological surgeon is afforded maximal freedom with resection, in that sacrifice of musculotendinous units and neurovascular structures can be ameliorated by tendon transfers and nerve and vein grafting. Planning for pedicled or free tissue transfer reduces complications by bringing in nonirradiated vascular tissue coverage for critical structures, reducing tension on wound closure, and eliminating dead space. The lower radiation dose in the modified Eilber protocol combined with the liberal use of flaps is paramount in achieving primary wound healing, decreasing hospital stay, and improving the final functional outcome.

In conclusion, a modified Eilber protocol is an excellent option for STS patients in terms of providing local control and decreasing major wound complications.

Received for publication March 19, 2004. Accepted for publication March 9, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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