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Experience of Interstitial Permanent I125 Brachytherapy for Extremity Soft Tissue Sarcomas
Clinical Oncology 26 (2014) 230e235 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Experience of Interstitial Permanent I125 Brachytherapy for Extremity Soft Tissue Sarcomas C. Ren, R. Shi, L. Min, W.L. Zhang, C.Q. Tu, H. Duan, B. Zhang, Y. Xiong Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, China Received 14 June 2013; received in revised form 31 October 2013; accepted 3 December 2013
Abstract Aims: Soft tissue sarcomas are uncommon, but relatively aggressive tumours. Although surgical resection remains the primary therapeutic modality for all localised tumours, brachytherapy combined with function-preserving excision is a popular treatment for extremity soft tissue sarcomas. The objective of this study was to evaluate the effect of interstitial permanent brachytherapy using I125 seeds in patients undergoing the combined modality in the management of soft tissue sarcomas at our institution. Materials and methods: Between January 2007 and January 2012, 110 adult patients aged 18e86 years (median ¼ 44 years) with extremity soft tissue sarcomas and who underwent interstitial permanent brachytherapy as part of the local treatment were included in this study. Treatment included wide local excision of the tumour and brachytherapy using a permanent I125 implantation. Complications were assessed in terms of wound complication and peripheral nerve damage. Results: After a median follow-up of 43.7 months, the local control, disease-free survival and overall survival for the entire cohort studied were 74, 54 and 77%, respectively. The actual rates of wound complications requiring reoperation and nerve damage were 4.5 and 1.8%, respectively. Conclusions: We conclude that interstitial permanent brachytherapy with I125 after function-preserving surgery results in a satisfactory outcome in patients with extremity soft tissue sarcomas and the complication rate is low. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Extremity; I125; interstitial brachytherapy; radiotherapy; soft tissue sarcoma
Introduction Soft tissue sarcomas (STS) are a group of uncommon, but relatively aggressive tumours. Extremity STS constitute about 1% of all cancers [1]. The local management of STS in adults includes surgery combined with radiotherapy or chemotherapy [2e7]. Although surgical resection remains the primary therapeutic modality for all localised tumours [8,9], brachytherapy (BRT) combined with functionpreserving excision is a popular treatment for extremity STS [10]. Postoperative external beam radiotherapy (EBRT) has played a vital role in the local control of STS and is an integral component of most treatment protocols. However, there are significant toxicities, such as tissue fibrosis, loss of Author for correspondence: H. Duan, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China. Tel: þ86-189-806-01402. E-mail address: [email protected] (H. Duan).
joint movement, neuritis and limb oedema associated with the high doses of EBRT required to achieve satisfactory local control [2e7]. BRT has emerged as an attractive treatment modality by which these complications may be reduced without compromising on adequate irradiation of the tumour bed [10]. The evidence of a low toxicity rate and a better tumour control rate due to BRT is the reason why we promote this treatment modality at our institution [10]. Furthermore, the overall treatment time is significantly decreased while maintaining a comparatively higher rate of local control. However, limited reports are available regarding the treatment modality of conventional functionpreserving excision followed by BRT with a permanent I125 implantation. Thus, in an attempt to further investigate the effects of BRT using permanent I125 implantation, we reviewed our experience of using BRT with permanent I125 implantation in adult patients associated with extremity STS. This retrospective study was approved by the Ethics Committee.
0936-6555/$36.00 Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2014.01.004
C. Ren et al. / Clinical Oncology 26 (2014) 230e235
231
Materials and Methods
Treatment
Between January 2007 and January 2012, 110 adult patients with non-metastatic extremity STS underwent conventional organ- and function-preserving surgery and perioperative interstitial BRT with permanent I125 implantation at our institution. Data such as age at diagnosis, gender, site, size, depth, histotype, grade and margin status of the tumour, the type of tumour, whether new onset or recurrent, and the dates on which the complications or death occurred were recorded. All tumours were diagnosed by experienced pathologists at our institution. Tumours were characterised as superficial or deep according to the involvement of the investing fascia. The specimen was examined in the presence of the surgeon and the tumour size was defined as the maximum diameter of the tumour. A positive microscopic margin of resection was defined as tumour cells present at or within 1 mm of the inked margins of resection. Because BRT is primarily a local treatment, disease control at the primary site was the primary end point evaluated in this 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; overall survival was calculated from the date of registration to the date of death due to any cause. The local control, DFS and overall survival rates were calculated using the KaplaneMeier method. Complications were assessed in terms of significant wound complication and peripheral nerve damage. The wound complication was defined as those wound problems requiring operative revision for coverage, persistent seroma requiring drainage and purulent wound discharge. Peripheral nerve damage was defined as paresthesias, loss of deep tendon reflexes, neuromotor toxicity as subjective weakness and impairment of function as an objective weakness.
All patients included in this study were treated with wide local excision (WLE) and perioperative interstitial BRT with permanent I125 implantation. The entire visible or palpable tumour was resected. Previous biopsy scars were included in the resection. When the tumour was intermuscular or intramuscular, resection included one or more of the involved muscle bundles. For tumours situated near neurovascular structures, resection was usually carried out. Similarly, stripping of the periosteum was needed for adequate resection in 13 (12%) of 110 patients. The margin was positive in 6/110 (5%) patients. After WLE, the tumour bed was demarcated by the surgeon. The number of I125 seeds was determined by the size of the tumour bed. Then, the I125 seeds were placed one by one in the tumour bed and generally the spacing was maintained at 1.5 cm. After WLE, when the normal tissue was far away from the tumour boundary, the spacing of I125 seeds was increased to 2 cm. When the normal tissue was closer to the tumour margin, the spacing of I125 seeds was decreased to 0.5e1 cm. When the tumour boundary was near to the neurovascular structures, the spacing of I125 seeds placed around the neurovascular structures was decreased to 0.5e1 cm. The number of I125 seeds implanted ranged from 15 to 45. The specific activity of I125 seeds ranged from 0.45 to 0.80 mCi per seed, with a median activity of 0.5 mCi. After the procedure, the surgical incisions were closed, either by primary closure or, if necessary, reconstruction of the surgical defect with regional or microvascular free flaps. The wound was primarily closed in 92% patients (101/110 patients) and required tissue transfer in 8% (9/110 patients). After removal of the drainage tube, computed tomography scans of the surgical area were input into the treatment planning system (TPS), the surgeon outlined the clinical target volume in the TPS, checked the dose distribution after implantation of the seeds and calculated the total dose received by the tumour bed compared with the standard treatment program in the
Fig 1. Seed distribution and isodose curve of I125 seed implants for a 53 year old male with right popliteal fossa liposarcoma.
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Table 1 Tumour characteristics Histological type
Histological grade Grade1
Liposarcoma Leiomyosarcoma Fibrosarcoma Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Other Total
Grade2
Grade3
Tumour depth
Tumour size
Site of primary tumour
Primary/recurrent
Superficial
5 cm
Upper extremity
Lower extremity
Primary
Recurrent
Deep
>5 cm
7 5 4 8 6 2
7 8 9 11 5 1
3 3 7 3 5 2
5 6 7 7 3 3
12 10 13 15 13 2
6 5 8 7 5 2
11 11 12 15 11 3
3 5 4 9 4 1
14 11 16 13 12 4
9 9 11 12 10 3
8 7 9 10 6 2
3 35
7 48
4 27
4 35
10 75
5 38
9 72
5 31
9 79
8 62
6 48
TPS to determine the need for the addition of EBRT. Patients who received additional EBRT were not included in this study. Figure 1 shows the distribution of the seeds and the isodose curve of I125 seed implantation for a 53 year old male with right popliteal fossa liposarcoma.
Results In this cohort, patients were 18e86 years of age with a median age of 44 years; 56% (n ¼ 62) were men and 44% (n ¼ 48) were women; 44% (n ¼ 48) of patients were treated for recurrent disease. In these 48 patients with recurrent STS, 37 patients received the first treatment in other hospitals. Of these 37 patients, 31 underwent surgery alone and six received EBRT as adjunctive therapy. Eleven patients received the first treatment in our hospital, of which seven received WLE only and four received EBRT. In the 110 patients, the lower extremities were most commonly involved (72%). The most common histological
types in this study cohort were synovial sarcoma (20%) and fibrosarcoma (18%), followed by a diverse group of histological types, including liposarcoma (15%), leiomyosarcoma (14%), epithelioid sarcoma (14%) and various other STS. Forty-three per cent of patients (n ¼ 48) had grade 2 lesions, 32% (n ¼ 35) had grade 1 lesions and 25% (n ¼ 27) had grade 3 lesions. The maximum diameter of the tumours ranged from 3 to 20 cm (median ¼ 7 cm). Thirtyfive per cent of patients (n ¼ 38) had tumours less than 5 cm maximum diameter. In 5% of patients (n ¼ 6) the surgical margins were positive and the others were negative. Table 1 presents the pertinent clinical and pathological information. All patients received treatment comprising conventional surgery in the form of WLE of the tumour followed by BRT with permanent I125 implantation. The number of I125 seed implants ranged from 15 to 45, with a median number of 30. After a median follow-up of 43.7 months (range 10e70 months), 59 patients were alive without disease, 25 patients were alive with disease and 26 patients had died. The local
Table 2 Results Prognostic factors
Overall Age Gender Size Depth Site Tumour Grade
40 years >40 years Male Female 5 cm >5 cm Superficial Deep Upper Lower Primary Recurrent 1 2 3
Local control Significance
Disease-free survival Significance
Overall survival Significance
n
%
P
%
P
%
P
70 36 74 62 48 38 72 35 75 31 79 62 48 35 48 27
75 72 77 68 68 76 88 67 74 73 74 72 78 75 69
0.821
58 51 55 52 68 46 57 52 58 51 58 48 56 56 49
0.491
75 77 75 77 78 75 77 76 80 74 85 65 77 79 70
0.814
0.306 0.367 0.010 0.934 0.880 0.564
0.774 0.035 0.614 0.560 0.290 0.766
0.876 0.643 0.895 0.508 0.004 0.685
C. Ren et al. / Clinical Oncology 26 (2014) 230e235
Fig 2. KaplaneMeier curve for local control comparing depth as a factor.
control, DFS and overall survival rates for the cohort studied were 74, 54 and 77%, respectively. The overall prognostic factors are summarised in Table 2. The local control, DFS and overall survival rates were analysed using the KaplaneMeier method using SPSS. Of the 110 patients treated, 29 patients developed recurrent disease within the BRT site. Patients with a superficial tumour had a local control rate of 88% compared with 67% in patients with a deep tumour (P ¼ 0.010; Figure 2). Patients with a tumour of less than 5 cm in diameter had a DFS rate of 68% compared with 46% in patients with a tumour of greater than 5 cm (P ¼ 0.035; Figure 3). Patients with a primary tumour had an overall survival rate of 85% compared with 65% in patients with a recurrent tumour (P ¼ 0.004; Figure 4). The age, gender, site of primary tumour (upper extremities versus lower extremities), grade of tumour and number of I125 seeds did not significantly influence the local control, DFS and overall survival. In the cohort, compartment syndrome occurred the day after surgery in one patient whose lesion was located in the forearm. Wound complications appeared in 4.5% (n ¼ 5) patients during the first 3
Fig 3. KaplaneMeier curve for disease-free survival comparing size as a factor.
233
Fig 4. KaplaneMeier curve for overall survival comparing the status (primary or recurrent) as a factor.
weeks after surgery. Of these five patients, two required debridement and the other three healed after drainage for 3 weeks. Nerve damage was assessed only in those patients who did not have nerve resection (n ¼ 103). Fifteen patients had nerve damage as limb paresthesias. No patient had loss of deep tendon reflexes or neuromotor toxicity. Complications such as loss of joint movement or bone fracture did not occur in any patient.
Discussion Treatment strategies for adults with STS have evolved over the years. With improvement in surgical and radiotherapeutic techniques, and with better understanding of the natural history of these tumours, the focus now is on organ and function preservation, with improvement of the quality of life of the patients. More ablative procedures, such as amputation and compartmental excision, have given way to conventional approaches such as WLE and radiation therapy without compromising on disease control [11e14]. However, most of the experience with adjuvant radiation therapy combined with surgery has revolved around the use of EBRT [15,16]. BRT, used either alone or combined with EBRT, has been an attractive alternative for the last two decades [17]. Some of the studies have reported that BRT, with or without EBRT, results in a satisfactory outcome in patients with extremity STS [18e20]. However, the reported BRT technique is a conventional technique that used after-loading catheters, placed surgically in the tumour bed [10,21]. Wang et al. [22] reported on interstitial I125 implantation to treat spinal metastatic and primary paraspinal malignancies. According to that study, the seeds were implanted under direct visualisation or percutaneously under computed tomography guidance. However, the manner in which BRT using interstitial permanent I125 implantation is carried out perioperatively for treating extremity STS is rarely reported. BRT with I125 seed implantation combined with WLE to treat extremity STS was started in our institution in 2007.
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The I125 sealed seed used in our institution is built using rod mark I125 isotope of palladium wire with a housing of high-density titanium alloy composition. The diameter of the titanium alloy is 0.8 mm, the length is 4.5 mm and the wall thickness is 0.05 mm. For the I125 seeds decayed by electron capture, the average energy of the photons emitted is 27.4 keV, with a half-life of 60.11 days. The initial dose rate is 7 cGy/h and its tissue penetration is 1.7e2.0 cm. Patients undergoing BRT usually leave hospital within 2 weeks of the operation. EBRT requires 5e7 weeks of treatment plus a 2e4 week interval from operations [21]. The evaluation of the tumour bed at the time of the tumour operation by a surgeon can far exceed any imaging modality in accuracy and the rapid dose fall-off with BRT spares more normal tissue than external radiation [21]. In most of the reports, BRT has only been used as a boost and not as the sole form of adjuvant radiation [23,24]. L. Siddharha et al. [10] reported that 155 patients had undergone WLE of primary tumour with BRT, with or without EBRT, with local control rates of 71%. The experience of Kaled [21] led to the concept of using BRT as an adjuvant therapy for STS. They reported local control rates of 84%. However, this improvement was limited to patients with primary highgrade histology. In our study, BRT with I125 as the only adjuvant radiation therapy was used in combination with WLE. In this study, involving 110 patients with extremity STS, the histology of the sarcoma ranged from grade 1 to grade 3. With a median follow-up of 43.7 months, the local control rate was 73.6%. This rate was significantly influenced by the depth of the tumour. The local control rate was 88% in superficial tumour and 67% in deep tumour. Tanabe et al. [25] reported that in 95 patients treated with preoperative EBRT, the 5 year local control rate was 83%. In this report, patients with a positive margin of resection had a local control rate of 62% compared with 91% for those with a negative margin. Kaled [21] reported the adverse effect of positive margins of resection. In those patients who accepted adjuvant BRT, the patients with a negative margin had a local control rate of 86% compared with 74% in those with a positive margin. At our institution, there were only six patients with a positive margin of the 110 patients who under WLE combined with permanent perioperative interstitial BRT using I125. Therefore, we did not attribute the margin status to the prognostic factors. However, in the six patients with a positive margin, four had local recurrence. In our study, the depth of the tumour significantly influenced the local control rate. However, few institutions have reported similar results. Laskar et al. [10] reported better DFS in patients with superficial tumours compared with deep-seated tumours. Authors have reported that a large tumour size is associated with poor DFS and overall survival [26,27]. In this study, we observed a higher rate of DFS in patients with tumours less than or equal to 5 cm (68% versus 46%; P ¼ 0.024). Our results also showed that the overall survival rate was better in patients with a primary tumour compared with those with a recurrent tumour (85% versus 65%; P ¼ 0.011). The effect of radiation therapy on wound complication rates has been widely reported [28]. In the study by Kaled
[21] the overall wound complication rate was 20%, with 12% of cases of wound complication requiring reoperation. In the present study, in 4.5% (n ¼ 5) of patients, wound complications appeared within 3 weeks of surgery. Of these five patients, two required debridement and the other three recovered after drainage for 3 weeks. The complication rate of 4.5% is far lower than the wound complication rate of EBRT and conventional BRT. We think that this advantage may be related to the following factors: (i) the radiation diameter of the I125 seed is only 1.7e2.0 cm. Therefore, it can achieve precise radiotherapy to the tumour bed, which reduces the exposure of normal tissue to these doses; (ii) the I125 was housed by a titanium alloy tube. Titanium alloy has good histocompatibility. The other complication encountered with adjuvant radiation is peripheral nerve damage [18]. In this study, 13% (n ¼ 15) of 103 patients had nerve damage in the form of limb paresthesias; impairment of joint mobility did not occur in any of the 103 patients. The incidence of peripheral complication was significantly lower compared with other studies [10]. The characteristic of the I125 is that it has a small radioactive shelf-life. The half-life of its emission source is only 60.1 days. After 1 year (6 half-life periods), only 1.6% of the original energy radiation is available as the remaining energy source and this is the main reason for the low rate of peripheral nerve complications. Regrettably, the existing study could not assess the cumulative dose received by the nerve trunk. More meticulous studies need to be carried out.
Conclusion In conclusion, we state that perioperative interstitial BRT using permanent I125 implantation is an effective modality with acceptable morbidity in the conventional management of extremity STS. Whether BRT using I125 is superior to EBRT or conventional BRT could not be determined from these data. More meticulous studies need to be carried out in order to formulate individualised interstitial BRT treatment using permanent I125 implantation.
References [1] Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8e29. [2] Pisters PWT, Leung DH, Woodruff J, et al. Analysis of prognostic factors in 1041patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996;14:1679e1689. [3] Stojadinovic A, Leung DH, Hoos A, et al. Analysis of the prognostic significance of microscopic margins in 2,084 localized primary adult soft tissue sarcomas. Ann Surg 2002;235:424e434. [4] Kattan MW, Leung DH, Brennan MF. Postoperative nomogram for 12-year sarcoma specific death. J Clin Oncol 2002;20: 791e796. [5] Gronchi A, Casali PG, Mariani L, et al. Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution. J Clin Oncol 2005;23:96e104.
C. Ren et al. / Clinical Oncology 26 (2014) 230e235 [6] Mariani L, Miceli R, Kattan MW, et al. Validation and adaptation of a nomogram for predicting the survival of patients with extremity soft tissue sarcoma using a three-grade system. Cancer 2005;103:402e408. [7] Coindre JM, Terrier P, Bui NB, et al. Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869e877. [8] Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197e203. [9] Pisters PW, Harrison LB, Woodruff JM, Gaynor JJ, Brennan MF. A prospective randomized trial of adjuvant brachytherapy in the management of low-grade soft tissue sarcomas of the extremity and superficial trunk. J Clin Oncol 1994;12: 1150e1155. [10] Siddharha L, Gaurav B, Ajay P. Perioperative interstitial brachytherapy for soft tissue sarcomas: prognostic factors and long-term results of 155 patients. Ann Surg Oncol 2007;14: 560e567. [11] Liebel SA, Tranbaugh RF, Wara WM, et al. Soft tissue sarcomas of the extremities. Survival and patterns of failure with conservative surgery and postoperative irradiation compared to surgery alone. Cancer 1987;50:1076e1083. [12] Cantin J, McNeer GP, Chu FC, et al. The problem of local recurrence after treatment of soft tissue sarcoma. Ann Surg 1968;168:47e53. [13] Martin RG, Butler JJ, Albores-Saavedra J. Soft tissue tumors: surgical treatment and results. Tumors of bone and soft tissue. Chicago: Year Book Medical Publishers; 1965. p. 333e348. [14] Shiu HN, Castro EB, Hajdu SI, et al. Surgical treatment of 297 soft tissue sarcoma of the lower extremity. Ann Surg 1975; 182:597e602. [15] Lindberg R, Martin R, Romsdahl M. Surgery and postoperative radiotherapy in the treatment of soft tissue sarcomas in adults. Am J Roentgenol Radium Ther Nucl Med 1975;123: 123e129. [16] Suit H, Russell W, Martin R. Sarcoma of soft tissue: clinical and histopathologic parameters and response to treatment. Cancer 1975;35:1478e1483. [17] Harrison L, Franzese F, Gaynor J, Brennan M. Long-term results of a prospective randomized trial of adjuvant
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brachytherapy in the management of completely resected soft tissue sarcomas of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 1993;27:259e265. Suit HD, Russel WO, Martin RG, et al. Management of patients with sarcomas of soft tissue in an extremity. Cancer 1973; 31:1255e1297. Lindberg RD, Martin RG, Romsdhal MM. Surgery and postoperative radiotherapy in the treatment of soft tissue sarcoma in adults. Am J Roentgenol 1975;123:123e129. Chaudhary AJ, Laskar S, Badhwar R. Interstitial brachytherapy in soft tissue sarcomas: the Tata Memorial Hospital experience. Strahlenther Onkol 1998;174(10):522e528. Kaled M. Adjuvant brachytherapy for primary high-grade soft tissue sarcoma of the extremity. Ann Surg Oncol 2002;9: 48e56. Wang J, Yuan H, Ma Q. Interstitial 125I seeds implantation to treat spinal metastatic and primary paraspinal malignancies. Med Oncol 2010;27:319e326. Schray M, Gunderson L, Sim F, Pritchard D, Shives T, Yeakel P. Soft tissue sarcoma: integration of brachytherapy, resection, and external irradiation. Cancer 1990;66:451e456. Thomas L, Delannes M, Stockle E, et al. Intraoperative interstitial iridium brachytherapy in the management of soft tissue sarcomas: preliminary results of a feasibility phase II study. Radiother Oncol 1994;33:99e105. Tanabe K, Pollock R, Ellis L, Murphy A, Sherman N, Romsdahl M. Influence of surgical margins on outcome in patients with preoperatively irradiated extremity soft tissue sarcomas. Cancer 1994;73:1652e1659. Tepper JE, Rosenberg SA, Glatstein E. Radiation therapy technique in soft tissue sarcomas of the extremity e policies of treatment at the NCI. Int J Radiat Oncol Biol Phys 1983; 8:263e293. Torosian MH, Fredrick C, Godbold J, et al. Soft tissue sarcomas. Initial characteristics and prognostic factors in patients with or without metastatic disease. Semin Surg Oncol 1980;4: 13e19. Alekhteyar KM, Leung DH, Brennan MF, et al. The effect of combined external beam radiotherapy and brachytherapy on local control and wound complications in patients with high grade soft tissue sarcomas of the extremity with positive microscopic margin. Int J Radiat Oncol Biol Phys 1996;36(2): 321e324.
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Experience of Interstitial Permanent I125 Brachytherapy for Extremity Soft Tissue Sarcomas C. Ren, R. Shi, L. Min, W.L. Zhang, C.Q. Tu, H. Duan, B. Zhang, Y. Xiong Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, China Received 14 June 2013; received in revised form 31 October 2013; accepted 3 December 2013
Abstract Aims: Soft tissue sarcomas are uncommon, but relatively aggressive tumours. Although surgical resection remains the primary therapeutic modality for all localised tumours, brachytherapy combined with function-preserving excision is a popular treatment for extremity soft tissue sarcomas. The objective of this study was to evaluate the effect of interstitial permanent brachytherapy using I125 seeds in patients undergoing the combined modality in the management of soft tissue sarcomas at our institution. Materials and methods: Between January 2007 and January 2012, 110 adult patients aged 18e86 years (median ¼ 44 years) with extremity soft tissue sarcomas and who underwent interstitial permanent brachytherapy as part of the local treatment were included in this study. Treatment included wide local excision of the tumour and brachytherapy using a permanent I125 implantation. Complications were assessed in terms of wound complication and peripheral nerve damage. Results: After a median follow-up of 43.7 months, the local control, disease-free survival and overall survival for the entire cohort studied were 74, 54 and 77%, respectively. The actual rates of wound complications requiring reoperation and nerve damage were 4.5 and 1.8%, respectively. Conclusions: We conclude that interstitial permanent brachytherapy with I125 after function-preserving surgery results in a satisfactory outcome in patients with extremity soft tissue sarcomas and the complication rate is low. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Extremity; I125; interstitial brachytherapy; radiotherapy; soft tissue sarcoma
Introduction Soft tissue sarcomas (STS) are a group of uncommon, but relatively aggressive tumours. Extremity STS constitute about 1% of all cancers [1]. The local management of STS in adults includes surgery combined with radiotherapy or chemotherapy [2e7]. Although surgical resection remains the primary therapeutic modality for all localised tumours [8,9], brachytherapy (BRT) combined with functionpreserving excision is a popular treatment for extremity STS [10]. Postoperative external beam radiotherapy (EBRT) has played a vital role in the local control of STS and is an integral component of most treatment protocols. However, there are significant toxicities, such as tissue fibrosis, loss of Author for correspondence: H. Duan, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China. Tel: þ86-189-806-01402. E-mail address: [email protected] (H. Duan).
joint movement, neuritis and limb oedema associated with the high doses of EBRT required to achieve satisfactory local control [2e7]. BRT has emerged as an attractive treatment modality by which these complications may be reduced without compromising on adequate irradiation of the tumour bed [10]. The evidence of a low toxicity rate and a better tumour control rate due to BRT is the reason why we promote this treatment modality at our institution [10]. Furthermore, the overall treatment time is significantly decreased while maintaining a comparatively higher rate of local control. However, limited reports are available regarding the treatment modality of conventional functionpreserving excision followed by BRT with a permanent I125 implantation. Thus, in an attempt to further investigate the effects of BRT using permanent I125 implantation, we reviewed our experience of using BRT with permanent I125 implantation in adult patients associated with extremity STS. This retrospective study was approved by the Ethics Committee.
0936-6555/$36.00 Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2014.01.004
C. Ren et al. / Clinical Oncology 26 (2014) 230e235
231
Materials and Methods
Treatment
Between January 2007 and January 2012, 110 adult patients with non-metastatic extremity STS underwent conventional organ- and function-preserving surgery and perioperative interstitial BRT with permanent I125 implantation at our institution. Data such as age at diagnosis, gender, site, size, depth, histotype, grade and margin status of the tumour, the type of tumour, whether new onset or recurrent, and the dates on which the complications or death occurred were recorded. All tumours were diagnosed by experienced pathologists at our institution. Tumours were characterised as superficial or deep according to the involvement of the investing fascia. The specimen was examined in the presence of the surgeon and the tumour size was defined as the maximum diameter of the tumour. A positive microscopic margin of resection was defined as tumour cells present at or within 1 mm of the inked margins of resection. Because BRT is primarily a local treatment, disease control at the primary site was the primary end point evaluated in this 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; overall survival was calculated from the date of registration to the date of death due to any cause. The local control, DFS and overall survival rates were calculated using the KaplaneMeier method. Complications were assessed in terms of significant wound complication and peripheral nerve damage. The wound complication was defined as those wound problems requiring operative revision for coverage, persistent seroma requiring drainage and purulent wound discharge. Peripheral nerve damage was defined as paresthesias, loss of deep tendon reflexes, neuromotor toxicity as subjective weakness and impairment of function as an objective weakness.
All patients included in this study were treated with wide local excision (WLE) and perioperative interstitial BRT with permanent I125 implantation. The entire visible or palpable tumour was resected. Previous biopsy scars were included in the resection. When the tumour was intermuscular or intramuscular, resection included one or more of the involved muscle bundles. For tumours situated near neurovascular structures, resection was usually carried out. Similarly, stripping of the periosteum was needed for adequate resection in 13 (12%) of 110 patients. The margin was positive in 6/110 (5%) patients. After WLE, the tumour bed was demarcated by the surgeon. The number of I125 seeds was determined by the size of the tumour bed. Then, the I125 seeds were placed one by one in the tumour bed and generally the spacing was maintained at 1.5 cm. After WLE, when the normal tissue was far away from the tumour boundary, the spacing of I125 seeds was increased to 2 cm. When the normal tissue was closer to the tumour margin, the spacing of I125 seeds was decreased to 0.5e1 cm. When the tumour boundary was near to the neurovascular structures, the spacing of I125 seeds placed around the neurovascular structures was decreased to 0.5e1 cm. The number of I125 seeds implanted ranged from 15 to 45. The specific activity of I125 seeds ranged from 0.45 to 0.80 mCi per seed, with a median activity of 0.5 mCi. After the procedure, the surgical incisions were closed, either by primary closure or, if necessary, reconstruction of the surgical defect with regional or microvascular free flaps. The wound was primarily closed in 92% patients (101/110 patients) and required tissue transfer in 8% (9/110 patients). After removal of the drainage tube, computed tomography scans of the surgical area were input into the treatment planning system (TPS), the surgeon outlined the clinical target volume in the TPS, checked the dose distribution after implantation of the seeds and calculated the total dose received by the tumour bed compared with the standard treatment program in the
Fig 1. Seed distribution and isodose curve of I125 seed implants for a 53 year old male with right popliteal fossa liposarcoma.
232
C. Ren et al. / Clinical Oncology 26 (2014) 230e235
Table 1 Tumour characteristics Histological type
Histological grade Grade1
Liposarcoma Leiomyosarcoma Fibrosarcoma Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Other Total
Grade2
Grade3
Tumour depth
Tumour size
Site of primary tumour
Primary/recurrent
Superficial
5 cm
Upper extremity
Lower extremity
Primary
Recurrent
Deep
>5 cm
7 5 4 8 6 2
7 8 9 11 5 1
3 3 7 3 5 2
5 6 7 7 3 3
12 10 13 15 13 2
6 5 8 7 5 2
11 11 12 15 11 3
3 5 4 9 4 1
14 11 16 13 12 4
9 9 11 12 10 3
8 7 9 10 6 2
3 35
7 48
4 27
4 35
10 75
5 38
9 72
5 31
9 79
8 62
6 48
TPS to determine the need for the addition of EBRT. Patients who received additional EBRT were not included in this study. Figure 1 shows the distribution of the seeds and the isodose curve of I125 seed implantation for a 53 year old male with right popliteal fossa liposarcoma.
Results In this cohort, patients were 18e86 years of age with a median age of 44 years; 56% (n ¼ 62) were men and 44% (n ¼ 48) were women; 44% (n ¼ 48) of patients were treated for recurrent disease. In these 48 patients with recurrent STS, 37 patients received the first treatment in other hospitals. Of these 37 patients, 31 underwent surgery alone and six received EBRT as adjunctive therapy. Eleven patients received the first treatment in our hospital, of which seven received WLE only and four received EBRT. In the 110 patients, the lower extremities were most commonly involved (72%). The most common histological
types in this study cohort were synovial sarcoma (20%) and fibrosarcoma (18%), followed by a diverse group of histological types, including liposarcoma (15%), leiomyosarcoma (14%), epithelioid sarcoma (14%) and various other STS. Forty-three per cent of patients (n ¼ 48) had grade 2 lesions, 32% (n ¼ 35) had grade 1 lesions and 25% (n ¼ 27) had grade 3 lesions. The maximum diameter of the tumours ranged from 3 to 20 cm (median ¼ 7 cm). Thirtyfive per cent of patients (n ¼ 38) had tumours less than 5 cm maximum diameter. In 5% of patients (n ¼ 6) the surgical margins were positive and the others were negative. Table 1 presents the pertinent clinical and pathological information. All patients received treatment comprising conventional surgery in the form of WLE of the tumour followed by BRT with permanent I125 implantation. The number of I125 seed implants ranged from 15 to 45, with a median number of 30. After a median follow-up of 43.7 months (range 10e70 months), 59 patients were alive without disease, 25 patients were alive with disease and 26 patients had died. The local
Table 2 Results Prognostic factors
Overall Age Gender Size Depth Site Tumour Grade
40 years >40 years Male Female 5 cm >5 cm Superficial Deep Upper Lower Primary Recurrent 1 2 3
Local control Significance
Disease-free survival Significance
Overall survival Significance
n
%
P
%
P
%
P
70 36 74 62 48 38 72 35 75 31 79 62 48 35 48 27
75 72 77 68 68 76 88 67 74 73 74 72 78 75 69
0.821
58 51 55 52 68 46 57 52 58 51 58 48 56 56 49
0.491
75 77 75 77 78 75 77 76 80 74 85 65 77 79 70
0.814
0.306 0.367 0.010 0.934 0.880 0.564
0.774 0.035 0.614 0.560 0.290 0.766
0.876 0.643 0.895 0.508 0.004 0.685
C. Ren et al. / Clinical Oncology 26 (2014) 230e235
Fig 2. KaplaneMeier curve for local control comparing depth as a factor.
control, DFS and overall survival rates for the cohort studied were 74, 54 and 77%, respectively. The overall prognostic factors are summarised in Table 2. The local control, DFS and overall survival rates were analysed using the KaplaneMeier method using SPSS. Of the 110 patients treated, 29 patients developed recurrent disease within the BRT site. Patients with a superficial tumour had a local control rate of 88% compared with 67% in patients with a deep tumour (P ¼ 0.010; Figure 2). Patients with a tumour of less than 5 cm in diameter had a DFS rate of 68% compared with 46% in patients with a tumour of greater than 5 cm (P ¼ 0.035; Figure 3). Patients with a primary tumour had an overall survival rate of 85% compared with 65% in patients with a recurrent tumour (P ¼ 0.004; Figure 4). The age, gender, site of primary tumour (upper extremities versus lower extremities), grade of tumour and number of I125 seeds did not significantly influence the local control, DFS and overall survival. In the cohort, compartment syndrome occurred the day after surgery in one patient whose lesion was located in the forearm. Wound complications appeared in 4.5% (n ¼ 5) patients during the first 3
Fig 3. KaplaneMeier curve for disease-free survival comparing size as a factor.
233
Fig 4. KaplaneMeier curve for overall survival comparing the status (primary or recurrent) as a factor.
weeks after surgery. Of these five patients, two required debridement and the other three healed after drainage for 3 weeks. Nerve damage was assessed only in those patients who did not have nerve resection (n ¼ 103). Fifteen patients had nerve damage as limb paresthesias. No patient had loss of deep tendon reflexes or neuromotor toxicity. Complications such as loss of joint movement or bone fracture did not occur in any patient.
Discussion Treatment strategies for adults with STS have evolved over the years. With improvement in surgical and radiotherapeutic techniques, and with better understanding of the natural history of these tumours, the focus now is on organ and function preservation, with improvement of the quality of life of the patients. More ablative procedures, such as amputation and compartmental excision, have given way to conventional approaches such as WLE and radiation therapy without compromising on disease control [11e14]. However, most of the experience with adjuvant radiation therapy combined with surgery has revolved around the use of EBRT [15,16]. BRT, used either alone or combined with EBRT, has been an attractive alternative for the last two decades [17]. Some of the studies have reported that BRT, with or without EBRT, results in a satisfactory outcome in patients with extremity STS [18e20]. However, the reported BRT technique is a conventional technique that used after-loading catheters, placed surgically in the tumour bed [10,21]. Wang et al. [22] reported on interstitial I125 implantation to treat spinal metastatic and primary paraspinal malignancies. According to that study, the seeds were implanted under direct visualisation or percutaneously under computed tomography guidance. However, the manner in which BRT using interstitial permanent I125 implantation is carried out perioperatively for treating extremity STS is rarely reported. BRT with I125 seed implantation combined with WLE to treat extremity STS was started in our institution in 2007.
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C. Ren et al. / Clinical Oncology 26 (2014) 230e235
The I125 sealed seed used in our institution is built using rod mark I125 isotope of palladium wire with a housing of high-density titanium alloy composition. The diameter of the titanium alloy is 0.8 mm, the length is 4.5 mm and the wall thickness is 0.05 mm. For the I125 seeds decayed by electron capture, the average energy of the photons emitted is 27.4 keV, with a half-life of 60.11 days. The initial dose rate is 7 cGy/h and its tissue penetration is 1.7e2.0 cm. Patients undergoing BRT usually leave hospital within 2 weeks of the operation. EBRT requires 5e7 weeks of treatment plus a 2e4 week interval from operations [21]. The evaluation of the tumour bed at the time of the tumour operation by a surgeon can far exceed any imaging modality in accuracy and the rapid dose fall-off with BRT spares more normal tissue than external radiation [21]. In most of the reports, BRT has only been used as a boost and not as the sole form of adjuvant radiation [23,24]. L. Siddharha et al. [10] reported that 155 patients had undergone WLE of primary tumour with BRT, with or without EBRT, with local control rates of 71%. The experience of Kaled [21] led to the concept of using BRT as an adjuvant therapy for STS. They reported local control rates of 84%. However, this improvement was limited to patients with primary highgrade histology. In our study, BRT with I125 as the only adjuvant radiation therapy was used in combination with WLE. In this study, involving 110 patients with extremity STS, the histology of the sarcoma ranged from grade 1 to grade 3. With a median follow-up of 43.7 months, the local control rate was 73.6%. This rate was significantly influenced by the depth of the tumour. The local control rate was 88% in superficial tumour and 67% in deep tumour. Tanabe et al. [25] reported that in 95 patients treated with preoperative EBRT, the 5 year local control rate was 83%. In this report, patients with a positive margin of resection had a local control rate of 62% compared with 91% for those with a negative margin. Kaled [21] reported the adverse effect of positive margins of resection. In those patients who accepted adjuvant BRT, the patients with a negative margin had a local control rate of 86% compared with 74% in those with a positive margin. At our institution, there were only six patients with a positive margin of the 110 patients who under WLE combined with permanent perioperative interstitial BRT using I125. Therefore, we did not attribute the margin status to the prognostic factors. However, in the six patients with a positive margin, four had local recurrence. In our study, the depth of the tumour significantly influenced the local control rate. However, few institutions have reported similar results. Laskar et al. [10] reported better DFS in patients with superficial tumours compared with deep-seated tumours. Authors have reported that a large tumour size is associated with poor DFS and overall survival [26,27]. In this study, we observed a higher rate of DFS in patients with tumours less than or equal to 5 cm (68% versus 46%; P ¼ 0.024). Our results also showed that the overall survival rate was better in patients with a primary tumour compared with those with a recurrent tumour (85% versus 65%; P ¼ 0.011). The effect of radiation therapy on wound complication rates has been widely reported [28]. In the study by Kaled
[21] the overall wound complication rate was 20%, with 12% of cases of wound complication requiring reoperation. In the present study, in 4.5% (n ¼ 5) of patients, wound complications appeared within 3 weeks of surgery. Of these five patients, two required debridement and the other three recovered after drainage for 3 weeks. The complication rate of 4.5% is far lower than the wound complication rate of EBRT and conventional BRT. We think that this advantage may be related to the following factors: (i) the radiation diameter of the I125 seed is only 1.7e2.0 cm. Therefore, it can achieve precise radiotherapy to the tumour bed, which reduces the exposure of normal tissue to these doses; (ii) the I125 was housed by a titanium alloy tube. Titanium alloy has good histocompatibility. The other complication encountered with adjuvant radiation is peripheral nerve damage [18]. In this study, 13% (n ¼ 15) of 103 patients had nerve damage in the form of limb paresthesias; impairment of joint mobility did not occur in any of the 103 patients. The incidence of peripheral complication was significantly lower compared with other studies [10]. The characteristic of the I125 is that it has a small radioactive shelf-life. The half-life of its emission source is only 60.1 days. After 1 year (6 half-life periods), only 1.6% of the original energy radiation is available as the remaining energy source and this is the main reason for the low rate of peripheral nerve complications. Regrettably, the existing study could not assess the cumulative dose received by the nerve trunk. More meticulous studies need to be carried out.
Conclusion In conclusion, we state that perioperative interstitial BRT using permanent I125 implantation is an effective modality with acceptable morbidity in the conventional management of extremity STS. Whether BRT using I125 is superior to EBRT or conventional BRT could not be determined from these data. More meticulous studies need to be carried out in order to formulate individualised interstitial BRT treatment using permanent I125 implantation.
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