10.1245/s10434-006-9137-2
Annals of Surgical Oncology 14:560-567 (2007)
© 2007 Society of Surgical Oncology
Perioperative Interstitial Brachytherapy for Soft Tissue Sarcomas: Prognostic Factors and Long-Term Results of 155 Patients
Siddhartha Laskar, MD1,
Gaurav Bahl, MD1,
Ajay Puri, MS2,
Manish G. Agarwal, MS2,
MaryAnn Muckaden, MD1,
Nikhilesh Patil, MD1,
Nirmala Jambhekar, MD3,
Sudeep Gupta, DM4,
Deepak D. Deshpande, PhD5,
Shyam K. Shrivastava, MD1 and
Ketayun A. Dinshaw, FRCR1
1 Department of Radiation Oncology, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai, India
2 Department of Surgery, Tata Memorial Hospital, Mumbai, India
3 Department of Pathology, Tata Memorial Hospital, Mumbai, India
4 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
5 Department of Medical Physics, Tata Memorial Hospital, Mumbai, India
Correspondence: Address correspondence and reprint requests to: Siddhartha Laskar, MD; E-mail: laskars2000{at}yahoo.com
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ABSTRACT
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Background: The goal of this study was to evaluate the efficacy of temporary interstitial brachytherapy (BRT) for patients undergoing combined modality management of soft tissue sarcomas (STS).
Methods: From January 1990 to December 2003, 155 adults 18–88 years of age (median = 42 years) with STS who had received BRT as part of locoregional treatment were included in this review. Sixty-four percent were males. Sixty-nine percent had primary lesions. Sixty percent had lesions involving the lower extremities. Spindle cell sarcoma (28%) and synovial sarcoma (16%) were the most common histologic types and 51% had grade III lesions. Treatment included wide local excision of primary tumor with BRT with or without external beam radiotherapy (EBRT).
Results: After a median followup of 45 months, the local control (LC), disease-free survival (DFS), and overall survival (OS) for the entire cohort was 71%, 57%, and 73%, respectively. DFS was superior for superficial tumors compared with that for deep tumors (96% vs. 54%, P =.02). Patients with a tumor less than 5 cm had superior OS (88% vs. 63%, P =.05). Cumulative radiotherapy dose greater than 60 Gy had a significant positive impact on LC (P = .003), DFS (P =.003), and OS (P =.048). Subcutaneous fibrosis (21%) was the major complication.
Conclusions: Temporary perioperative iridium-192 interstitial BRT with or without EBRT after function-preserving surgery results in satisfactory outcome in patients with STS. Both low dose rate and high dose rate BRT are equivalent in terms of disease control and complications when used alone or in combination with EBRT. BRT results in fewer complications compared with the combination of BRT and EBRT.
Key Words: Soft tissue sarcoma • Radiotherapy • Interstitial brachytherapy
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INTRODUCTION
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Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumors arising from the supporting extraskeletal mesenchymal tissues of the body. They are a group of relatively uncommon, but aggressive, neoplasms that represent approximately 1% of all cancers. Local management of adult STS includes surgery combined with radiotherapy. Optimal therapy aims at eradicating local disease with minimal functional disability. Although surgical resection remains the primary therapeutic modality for all localized tumors, it is now established that conservative function-preserving excision followed by adjuvant irradiation provides adequate local control with good cosmetic and functional outcome and quality of life.
Postoperative external beam radiotherapy (EBRT) has played a pivotal role in the local control of these tumors and is an integral component of most treatment protocols. However, there are significant late toxicities associated with the high doses of EBRT required to achieve satisfactory local control (LC), such as tissue fibrosis, loss of joint motion, neuritis, and limb edema. Brachytherapy (BRT) has emerged as an attractive modality by which these complications may be reduced without compromising adequate irradiation of the tumor bed. This treatment approach, used alone or in combination with EBRT, delivers high doses of radiation to the tumor volume in a very precise and localized manner while sparing the nearby normal tissues. Furthermore, the overall treatment time is significantly shortened while maintaining a comparable high rate of LC. The ability to spare normal tissues significantly allows BRT to be used postoperatively with recurrent disease in previously irradiated patients. In an attempt to further define the efficacy of BRT, we reviewed our experience with BRT in adults with STS.
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PATIENTS AND METHODS
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From January 1990 to December 2003, 155 adults with nonmetastatic STS underwent conservative organ- and function-preserving surgery and perioperative interstitial BRT with or without EBRT at our institution. Patients were 18–88 years of age with a median age of 42 years at presentation. There were 99(64%) males and 56(36%) female patients. Approximately one-third (31%) were treated for recurrent disease. The lower extremities were most commonly involved (60%), followed by the upper extremities (19%), the chest and abdominal walls (19%), and the head and neck region (1%). The most common histologic types in this study were spindle cell sarcoma (28%) and synovial sarcoma (16%), followed by a diverse group of histologies, including liposarcoma (14%), malignant fibrous histiocytomas (9%), fibrosarcoma (7%), malignant peripheral nerve sheath tumor (6%), rhabdomyosarcoma (5%), lieomyosarcoma (5%), and various other soft tissue sarcomas. Seventy-nine patients (51%) had grade III, 38 (25%) had grade II, and 38 (25%) had grade I lesions. The diameter of the tumors ranged from 2 to 20 cm (median = 7 cm). Sixty-seven patients (43%) had tumors less than 5 cm in maximum diameter. In eight patients (5%) the surgical margins were positive and in six (4%) they were close. The tumor size was determined from the gross pathologic description when available, or else from the initial clinical description. Tumor grade, histologic subtype, and margins were obtained from the microscopic description by experienced pathologists. Table 1
presents the pertinent clinical and pathologic patient information.
All patients received treatment consisting of conservative surgery in the form of wide local excision (WLE) of the tumor followed by postoperative radiotherapy. The skin closure was primary in 142 (91%) of patients while 11 (7%) underwent reconstruction of the skin defect with a pedicle graft and two patients had a split skin graft. Fifty-five patients (36%) were treated with radical BRT alone while 100 patients (64%) received a combination of BRT and EBRT (EBRT dose range = 20–50 Gy, median = 46 Gy). While in 98 (63%) patients BRT was delivered using low dose rate (LDR), 57 (37%) were treated with high dose rate (HDR) BRT. The BRT dose varied depending on whether the patient would receive further EBRT. The median cumulative dose of radiation in the group receiving BRT and EBRT was 69.9 Gy. In the group receiving BRT alone, the median doses were 39 Gy and 34.5 Gy in the LDR and HDR groups, respectively.
Brachytherapy Technique
All patients included in this study were treated with temporary perioperative interstitial BRT using iridium-192. After WLE the tumor bed was demarcated by both the surgeon and the radiation oncologist using radiopaque surgical clips. Plastic afterloading catheters were introduced into the tumor bed using 16-gauge stainless-steel needles. The implanted area generally included the tumor bed with a 2-cm radial margin. The longitudinal margin depended on the intent of BRT. When BRT was intended to be used as a boost along with EBRT, the margin was 2 cm beyond the tumor bed, while the margin was increased to 3–4 cm if the plan was to use radical BRT alone. The catheters were placed parallel to each other at a distance of 1.0–1.5-cm intervals. No effort was made to include the drain sites within the implanted volume. A single-plane arrangement was used for all patients. Catheters were inserted at at a depth of approximately 5 mm into the tumor bed to avoid underdosage of the tumor bed. In situations in which the catheters could not be anchored to the tumor bed, resorbable sutures were used to secure the catheters onto the tumor bed. If required, gel-foam or thin muscle flaps were interposed between the catheter plane and neighboring critical structures. Finally, catheters were secured in position using stainless-steel buttons and plastic beads (Figs. 1 and 2). After the procedure, the surgical incision was closed either by primary closure or, if necessary, with the reconstruction of the surgical defect with regional or microvascular free flaps. Orthogonal radiographs were taken on the fourth or fifth postoperative day for dosimetry and treatment planning. Treatment was generally started on the same day as dosimetry. The EBRT + BRT dose was based on the intent of BRT (radical vs. boost) and the BRT dose rate (HDR vs. LDR).
Statistical Analysis
Followup information was abstracted from patients’ hospital records and from an existing database of patients undergoing BRT. Because BRT is primarily a local treatment, disease control at the primary site/tumor bed was the primary endpoint evaluated in the study. Local failure was defined as recurrence or progression within or at the margin of the irradiated field. Disease-free survival (DFS) was calculated from the date of registration to the date of recurrence of disease at any site, and overall survival (OS) was calculated from the date of registration to the date of death due to any cause. LC, DFS, and OS rates were calculated using the Kaplan–Meier method. Multiple-covariate analysis was performed using the stepwise Cox proportional hazards regression model. The hazard ratios (HR) with the 95% confidence interval (CI) were calculated. Complications were recorded as either acute or chronic if they occurred within three months or more than 3 months after completion of treatment, respectively. Events were scored according to the Radiation Therapy Oncology Group (RTOG) late radiation morbidity scoring system.
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RESULTS
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After a median followup of 45 months (range = 1–132 months), 125 (81%) patients were alive without disease, 12 (8%) patients were alive with disease, and 18 (11%) patients had died due to disease. The LC, DFS, and OS for the whole cohort were 71%, 57%, and 73%, respectively. The overall results/ prognostic factors are summarized in Table 2. Table 3a and 3b highlights the patterns of failure according to tumor characteristics and type of radiotherapy treatment.
Local Control
Of the 155 patients treated, 10 developed recurrent disease within the BRT site. The 5-year LC rate for the whole group was 71%. Patients with a maximum tumor diameter less than or equal to 5 cm had a LC of 87% vs. 62% for those with a tumor diameter greater than 5 cm (P = .79). Patients with superficial and deep tumors had LC rates of 96% and 54%, respectively (P = .20). Age at presentation, gender, site of primary tumor (upper extremities vs. lower extremities vs. trunk), grade of the tumor, and type of tumor (primary vs. recurrent) did not significantly influence the LC (Table 2
). Furthermore, patients with microscopically positive and negative surgical margins had similar LC rates of 45% and 51%, respectively (P = .29). Patients receiving a combination of BRT and EBRT had LC of 74% compared with 63% (P = .13) for those receiving BRT alone. Among the 100 patients treated with a combination of BRT and EBRT, the cumulative radiation dose significantly influenced the incidence of local disease recurrence. The LC rate was significantly superior in the group receiving cumulative radiation doses equal to or greater than 60 Gy (P = .003) (Fig. 3). This retained significance on multivariate analysis, and the hazard ratio (HR) for local failure in the group of patients receiving a cumulative RT dose of less than 60 Gy was 3.72 (95% CI: 1.35–9.51) (Table 5). In this same subgroup, there was no statistically significant difference in the LC rates between the patients who received BRT using HDR versus those receiving LDR BRT (96% vs. 73%, P =.72). Of the 55 patients who received radiotherapy in the form of radical BRT alone, the LC rates were 65% and 50% in the groups receiving LDR and HDR BRT, respectively (P =.44).
Disease-Free and Overall Survival
The 5-year DFS and OS for the entire group were 57% and 73%, respectively. Eighteen patients (12%) died due to disease, 10 (6%) were alive with disease, and the remaining 127 (82%) were alive without evidence of disease at the time of analysis. Fifteen of the 20 (75%) patients who had developed distant metastasis died due to the disease. All three patients who had developed distant metastasis as well as a local recurrence died of their disease. Five of the seven patients (71%) who had failed locally were alive with disease, and the other two patients with local recurrence, who had been treated with salvage surgery and further radiotherapy, were alive without disease. The most common site of distant metastases was the lungs.
Patients with a maximum tumor diameter less than or equal to 5 cm had an OS of 88% vs. 63% for those with lesions greater than 5 cm (P = .05). Although there was a clear difference in the DFS between these two groups (78% vs. 46%), this did not attain statistical significance (P = .22). Patients with superficial tumors had a better outcome than those with deep ones, the DFS and OS being 90% vs. 42% (P = .05) (Fig. 4) and 93% vs. 67% (P = .18), respectively. Age at presentation, gender, site of primary tumor (upper extremities vs. lower extremities vs. trunk), grade of the tumor, and type of tumor (primary vs. recurrent) did not significantly influence the DFS or OS (Table 2). The DFS was 50% vs. 59% (P = .38) and OS was 52% vs. 79% (P = .76) for patients receiving BRT alone and. BRT + EBRT, respectively. In patients treated with a combination of BRT and EBRT, those who had received a cumulative dose greater than 60 Gy had a significant improvement in DFS compared with those receiving doses less than 60 Gy (P = .003). Similarly, the OS was 36% vs. 84% between those receiving doses less than 60 Gy versus more (P = .04) (Fig. 5). On multivariate analysis, the hazard ratio (HR) for death in the group of patients receiving a cumulative RT dose of less than <60 Gy was 3.39 (95% CI: 0.98–6.39) (Table 4). Within this same subgroup, the patients who received LDR BRT had a DFS of 58% vs. 84% for HDR (P = .73). Similarly, the OS was 78% vs. 89% (P = .84), respectively, between the two groups. Among the 55 patients receiving radiotherapy in the form of BRT alone, the DFS was 52% vs. 44% (P = .58) between LDR and HDR BRT, respectively. Similarly, the OS was 56% vs. 40% (P = .16) between LDR and HDR BRT.
Complications (Table 5 Subcutaneous fibrosis was the major late sequelae (21%) followed by distal limb edema (10%) and wound dehiscence (6%). Impaired joint mobility was documented in 5% patients. The incidence of subcutaneous fibrosis, distal limb edema, wound dehiscence, and impairment of joint mobility was more in the group receiving BRT + EBRT compared to BRT alone (30% vs. 5%, 15% vs. nil, 7% vs. 5%, and 8% vs. nil. respectively).
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DISCUSSION
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Treatment strategies for adults with soft tissue sarcomas have evolved over the years. With improvement in surgical and radiotherapeutic techniques and with better understanding of the natural history of these tumors, the focus now is on organ and function preservation with improvement of quality of life of the patients. More ablative procedures like amputation and compartmental excision have given way to conservative approaches like WLE and radiation therapy without compromising on disease control.1–4 Radiation therapy in the form of EBRT and BRT, used either alone or in combination, has been established as an important component of these multimodal approaches in the management of STS. Experiences of Suit et al.,5 Martin et al.,3 and Lindberg et al.6 lead to the concept of limited surgery and high-dose radiation therapy in STS resulting in LC rates of 80%–90%. In our earlier publication from the Tata Memorial Hospital,7 we had reported two-year local control rates of 86% and 82%, respectively for patients receiving BRT + EBRT and BRT alone, respectively. In our current series we report LC, DFS, and OS of 71%, 57%, and 73%, respectively, after a longer median followup of 45 months. Pisters et al.,8 in a randomized trial comparing WLE versus WLE + BRT, showed superior results in the group receiving BRT. They reported a LC rate of 91% which is comparable to local control rates reported in other series using postoperative EBRT.9,10 The current series reports LC rates of 62.8% and 73.7% (P = .1) for patients receiving BRT alone and BRT + EBRT, respectively. Brennen et al.,11 Harrison et al.,12 and Habrand et al.13 have also demonstrated similar LC rates with the use of BRT. However, in most of their trials the advantage of BRT was restricted primarily to high-grade tumors. The possible explanation for the absence of LC advantage with BRT for low-grade tumors has been ascribed to the slower progress along the cell cycle for these tumors compared to the high-grade tumors. As a consequence, the total duration of the BRT treatment (4–5 days) may not be able to catch all the tumor cells in their radiosensitive phase. In the randomized trial by Pisters et al.,8 the authors reported no additional advantage of interstitial BRT for disease control in low-grade tumors. In the current study a significant proportion of patients received HDR BRT (over 4–5 days). Suit et al.14 reported a strong correlation between tumor grade and disease-free survival, with DFS of 83% for grade I and 17% for grade III tumors. In a study from the Memorial Sloan Kettering Cancer Centre (MSKCC) by Alekhteyar et al.,15 there was no difference in the two-year actuarial LC rate between the BRT + EBRT group (90%) and the BRT-alone group (82%) (P = .32). However, for patients with positive resection margins, the use of BRT + EBRT produced better local control than BRT alone (P = .08). In our study only 8 of the 155 patients had positive resection margins and we observed no difference in outcome compared with those with negative margins. However, statistical interpretation of this small number of patients with microscopically positive margins may be erroneous and we do not base any conclusions on this finding.
It has been well established that large tumor size is associated with poor DFS and OS.16,17 Authors have reported inferior LC rates in patients with tumors equal to or greater than 5 cm compared with tumors less than or equal to 5 cm. It has also been observed that tumors equal to or greater than 10 cm were associated with a greater rate of distant metastasis. In our present series we observed a higher rate of distant metastases among patients with tumors equal to or greater than 5 cm compared with smaller tumors, resulting in an inferior OS (63.3% vs. 88%, P =.05). Our results also showed better DFS in patients with superficial tumors compared to deep-seated tumors (90.3% vs. 41.5%, P = .05). The incidence of distant metastasis is higher among patients with local failure compared with those with disease locally controlled (30% vs. 14%, P = .17). Although this difference did not achieve statistical significance, there seems to be a definite trend toward increased incidence of distant metastasis in patients with local failure. Other investigators have also observed a reduction in the incidence of distant metastasis with improvement in local disease control.12,18,19
The impact of radiation therapy on wound complication rates has been widely evaluated in the past. In the current study the most significant complication was subcutaneous fibrosis (21%). There was no difference in the complication rates between patients undergoing primary wound closure versus those who underwent reconstructive surgery. In a randomized trial from MSKCC20 of BRT vs. no further RT after complete tumor excision, the authors reported wound complication rates of 24% in the BRT group and 14% in the no-BRT group (P = .13). However, they highlighted that wound reoperation rates after BRT were higher if the width of the skin excised during surgery was more than 4 cm. Arbeit et al.21 reported a significantly higher complication rate in the BRT versus the no-BRT groups (48% vs. 16%, P = .01), whereas Ormsby et al.22 found no difference in the complication rates between the two arms (14% vs. 10%). This difference in complication rates between the two studies was attributed to the difference in the delay in loading the radioactive sources after the surgery in the two studies. In the Arbeit et al. study21 the mean time for loading was 4.3 days compared with 6.1 days in the Ormsby et al. study.22 The time-dependent effect of radiation damage on wound healing has been demonstrated in animal models. Devereux et al.23 showed that timing of radiation therapy and the combination of antineoplastic agents could impair normal wound healing. They suggested that radiation or antineoplastic drugs used seven days before or after surgery could inhibit wound healing. This was attributed to the inhibition of newly synthesized collagen as determined using hydroxyproline assays and force tension curves. In a randomized trial of preoperative versus postoperative radiotherapy reported by O’Sullivan et al.,24 the authors reported a higher acute wound complication rate in the preoperative versus the postoperative group (35% vs. 17%, P = .01). At our institute the policy is to start radiation treatment on the fourth or fifth day after surgery.
In conclusion, we state that interstitial BRT with or without EBRT is an effective modality in the conservative management of STS. Future studies using BRT should try to stratify patients into treatment groups based on clinicopathologic factors so that selected patients could be treated with BRT alone without compromising on disease control rates, especially in the current context of increasing use of systemic chemotherapy along with radiation therapy in patients with high-grade extremity STS.
Received for publication April 12, 2006.
Accepted for publication June 19, 2006.
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REFERENCES
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ABSTRACT
INTRODUCTION
