Int J Clin Oncol DOI 10.1007/s10147-013-0640-8
ORIGINAL ARTICLE
Radiofrequency ablation for the treatment of recurrent bone and soft-tissue sarcomas in non-surgical candidates Koichiro Yamakado • Akihiko Matsumine • Tomoki Nakamura • Atsuhiro Nakatsuka Haruyuki Takaki • Takao Matsubara • Kunihiro Asanuma • Akihiro Sudo • Yoshiki Sugimura • Hajime Sakuma
•
Received: 25 September 2013 / Accepted: 4 November 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Aims The aim of this study was to evaluate the safety and clinical utility of radiofrequency ablation (RFA) retrospectively in non-surgical candidates with recurrent bone and soft-tissue sarcomas. Methods Percutaneous RFA was used in 52 patients (21 female, 31 male; mean age, 52.2 ± 21.1 years; range 10–87 years) with recurrent bone and soft-tissue sarcomas. The number of tumors was 3 or fewer in 23 patients (44.2 %) and 4 or more in the others, with a mean maximum tumor diameter of 3.0 ± 3.7 cm (range 0.5–18 cm). Safety, tumor control, and prognosis were evaluated. Results All tumors were ablated after RFA in 21 patients (40.4 %, 21/52), although 14 experienced re-recurrence. Tumors were controlled in 8 cases of recurrence by repeat RFA (n = 7) and surgical intervention (n = 1). Therefore, 15 patients (28.8 %, 15/52) were tumor-free at the end of follow-up (mean follow-up 25.5 ± 24.2 months; range 3.9–117 months). Residual tumors were found after RFA in
K. Yamakado (&) A. Nakatsuka H. Takaki Department of Interventional Radiology, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan e-mail: [email protected] A. Matsumine T. Nakamura T. Matsubara K. Asanuma A. Sudo Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Japan Y. Sugimura Department of Urology, Mie University School of Medicine, Tsu, Japan H. Sakuma Department of Diagnostic Radiology, Mie University School of Medicine, Tsu, Japan
the other 31 patients (59.6 %, 31/52). Overall survival rates were 73.4 % (95 % CI 61.0–85.9 %) at 1 year, 39.3 % (95 % CI 23.6–54.9 %) at 3 years, and 34.3 % (95 % CI 18.0–50.7 %) at 5 years in all patients. Recurrence-free interval (p = 0.040), tumor number (p = 0.0094), and complete tumor ablation (p \ 0.0001) were detected as significant prognostic factors in univariate analysis. The latter two factors were significant in multivariate analysis. The rate of major complications was 0.9 %. Conclusions RFA is a safe and useful therapeutic option for treatment of recurrent bone and soft-tissue sarcomas. Prognostic factors found in this study will help to identify those patients who would benefit from RFA. Keywords Bone sarcoma Soft tissue sarcoma Recurrence Radiofrequency ablation Prognosis
Introduction Sarcomas account for approximately 1 % of all adult malignancies and 15 % of pediatric malignancies [1]. Even after complete remission following the primary treatment, 30–35 % of bone sarcoma patients and about 50 % of soft-tissue sarcoma patients experience local or systemic relapse [2–6]. Although standard treatments for recurrent sarcomas have not been established, complete removal of all tumors irrespective of local or systemic recurrence is advocated to achieve long-term survival [1–3, 6–9]. Nevertheless, not all patients benefit from surgical treatment. Although the lung is the most frequent site for distant metastasis, only 25–30 % of patients with lung metastases benefit from metastasectomy because of the multiplicity of lung metastases, associated recurrences at other sites, and comorbid diseases [10].
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Systemic chemotherapy has minimal impact on the survival of most patients with recurrent sarcomas. Most patients die within 1 year, with a median survival time of 8.3–14.9 months after the diagnosis of recurrence [3, 4, 11]. Therefore, it is important to explore a new treatment strategy for recurrent sarcomas in non-surgical candidates. Although guidelines suggest the use of radiofrequency ablation (RFA) for the treatment of advanced sarcoma [1, 7], few reports have described its clinical utility in controlling recurrent sarcomas or its impact on patient prognosis [10, 12]. This study retrospectively evaluated the clinical utility of RFA in non-surgical candidates with recurrent bone and soft-tissue sarcomas.
Materials and methods Study design and patients Our institutional review board approved this study and waived the requirement for informed consent to use data
for research purposes. Informed consent to perform RFA was obtained appropriately from the patient or a parent before all treatments. Application of RFA for recurrent sarcomas was determined by discussion between surgeons, urologists, orthopedic surgeons, medical and radiation oncologists, and interventional radiologists. RFA was performed when tumors were considered unresectable, when there was a risk of causing severe complications after surgery, or when patients refused to undergo surgical intervention. We analyzed a prospectively collected computerized database. Between September 2000 and September 2012, 54 consecutive patients received RFA for the treatment of recurrent bone and soft-tissue sarcomas at our institution (Tables 1, 2; Fig. 1). Two patients were excluded from this study because the follow-up period was shorter than 6 months. 52 patients were included in this study. Twentyfive patients (48.1 %, 25/52) with lung metastases had been included in previous studies [10, 13]. All patients were judged as non-surgical candidates except one patient, a 10-year-old girl with recurrent neck tumor. She and her parents refused surgery for cosmetic reasons.
Table 1 Patient and tumor backgrounds Variables
All patients
Complete ablation group
Residual tumor group
p value
Number
52
21
31
Female/male
21/31
9/12
11/20
0.77
Age (years)
52.2 ± 21.1 (range 10–87)
51.9 ± 21.9 (range 10–87)
51.8 ± 22.2 (range 11–81)
0.78
B50 years/[50 years
22/30
9/12
11/20
0.77
Patient characteristics
Primary tumor Lower extremities/retroperitoneum/others
25/10/17
8/6/7
17/4/10
Bone/soft tissue
16/36
6/15
10/21
0.21
LMS/OS/LS/MFH/CS/Others
11/8/6/6/5/16
3/2/4/3/3/6
8/6/2/3/2/10
0.50
39.8 ± 39.8 (range 0–134)
36.1 ± 37.1 (range 2–125)
34.4 ± 39.2 (range 0–130)
0.061
30/22
11/10
19/12
0.58
25/27 23/29
10/11 7/14
15/16 16/15
[0.99 0.26
[0.99
Recurrent tumors Recurrence-free period (months) B2 years/[2 years Previous chemotherapy, yes/no Previous surgery, yes/no Involved organs
0.27
Lung
30
9
20
Lung and other organ
9
5
5
0.16 [0.99
Retroperitoneum
9
5
2
Body wall
2
2
2
[0.99
Mediastinum
2
0
2
0.51
Local recurrence/Metastasis
9/43
6/15
3/28
0.13
Maximum tumor diameter (cm)
3.0 ± 3.7 (range 0.5–18)
2.2 ± 1.6 (range 0.6–6.8)
3.5 ± 4.4 (range 0.5–18.0)
0.51
46/6
20/1
26/5
0.38
12/18/22
11/10/0
1/8/22
B5 cm/[5 cm
0.074
Tumor number Single/2–6/C 7
LMS leiomyosarcoma, OS osteosarcoma, LS liposarcoma, MFH malignant fibrous histiocytoma, CS chondrosarcoma
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\0.0001
Int J Clin Oncol Table 2 Overall survival rates based on variables
Patient number
Survival rate (%) 1-year
3-year
MST (months)
p value
5-year
Gender Female
20
75.6
42.0
42.0
28
Male
32
72.0
38.1
19.1
24.7
0.43
B50 years
22
76.6
49.1
40.9
35.7
[50 years
30
70.6
31
31
19.1
Lower extremities
25
52.4
37.5
37.5
17.8
Others
27
92.2
37.7
28.3
27.7
16 36
69 75.6
53.7 31.9
35.8 31.9
46.2 19.1
0.67
0.035
Age 0.51
Primary tumor location 0.49
Bone or soft tissue Bone Soft tissue Recurrence-free period B2 years
30
63.3
27.2
27.2
17.2
[2 years
22
90.2
60.2
48.2
46.2
Chemotherapy for recurrent tumor Yes
25
59.5
44.6
37.2
17.2
No
27
87.3
35
35
27.7
0.32
Surgery for recurrent tumor Yes
23
76
23.5
23.5
24.7
0.7
No
29
71.4
46.9
39.1
27.7
Lung alone
29
60.9
30.4
22.8
17.2
Others
23
91.1
53.2
53.2
68.8
9 43
100 68.2
55.6 35.2
55.6 29.3
68.8 18.3
0.13
0.44
Involved organs 0.1
Treated tumors Local recurrence Metastasis
Maximum tumor diameter (cm) B5
46
75
40.1
34.4
27.7
[5
6
53.3
26.7
26.7
15.6
B3
23
95.7
51.9
44.5
46.2
C4
29
54.8
32
32
15.6
64.1
68.8
Tumor number 0.019
Treatment results MST median survival time, NA not applicable
Curative
21
Palliative
31
The patients examined in this study were 20 females and 32 males with mean age of 52.2 ± 21.1 years (range 10–87 years). The primary tumors were bone sarcoma in 16 patients (30.8 %, 16/52) and soft-tissue sarcoma in the other 36 patients (36/52, 69.2 %). The histology varied as shown in Table 1. Pretreatment workup included brain, lung, abdomen, and pelvic computed tomography (CT) studies with and without contrast medium administration (Fig. 2a). When primary lesions were in extremities, images including the primary
100 53.6
73.2 15.3
NA
\0.0001
13.4
resected regions were acquired. The diagnosis of recurrent tumors was established by biopsy in 38 patients (73.1 %, 38/52), and by serial CT or magnetic resonance (MR) imaging studies in the other patients. New tumors that increased in size over time were regarded as recurrent sarcomas. Recurrent tumors were found within 2 years after the initial treatment in 30 patients (57.7 %, 30/52) and beyond 2 years in the other 22 patients (42.3 %, 22/52). The most frequent site of recurrence was the lung, found in 39 patients (75.0 %, 39/52). Local recurrence in the primary
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Int J Clin Oncol Fig. 1 Courses of treatment in patients who underwent radiofrequency ablation for recurrent bone and soft-tissue sarcoma. RFA radiofrequency ablation, Chemo chemotherapy, BSC best supportive care
tumor site was found in 9 patients (17.3 %, 9/52). The tumor number was single in 12 patients (23.1 %, 12/52), 2–6 in 18 patients (34.6 %), and 7 or more in the other 22 patients (42.3 %, 22/52). The mean maximum tumor diameter was 3.0 ± 3.7 cm (range 0.5–18 cm) at the time of initial RFA. RFA RFA was performed on an inpatient basis under general anesthesia in 2 children (10 and 12 years) and under local anesthesia in the 50 adult patients. Antibiotics (Cefazolin; Astellas Pharma Inc., Tokyo, Japan) were administered prophylactically before and for 1–2 days after RFA. Three interventional radiologists (KY, AN, HT) performed the RFA. Internally cooled RF electrodes (Cool-Tip RFA System; Valleylab, Boulder, CO, USA) were placed into each tumor based on the tumor size and shape under realtime CT fluoroscopic guidance (Aquilion; Toshiba Medical Systems Corp., Nasu, Japan) (Fig. 2b). After connecting the electrode to a generator (Series CC-1, RF 3000; Valleylab, Boulder, CO, USA), RF energy was applied for 12 min using an impedance-control algorithm. When target tumors were multiple, 2–3 tumors were treated per session. When the tumor was located adjacent to a critical organ, such as the bowel, distilled water (Otsuka Pharmaceutical,
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Tokyo, Japan) or hyaluronic acid gel (Adant, Meiji Seika Pharma Co. Ltd., Tokyo, Japan) was injected between the tumor and the critical organ in order to separate them (Fig. 2b) [14, 15]. CT or MR studies with and without contrast enhancement were performed within 1 week of RFA to evaluate the antitumor effects. Complete disappearance of tumor enhancement was regarded as complete tumor necrosis (Fig. 2c). When tumor enhancement remained after RFA, the RFA was repeated during the subsequent week provided repeat RFA was judged to be safe.
Follow-up and complications Physical examination and laboratory tests were performed every month. CT and MR studies were conducted with and without contrast enhancement every 3–4 months on an outpatient basis (Fig. 2c, d). Enlargement of an ablative tumor was regarded as local tumor progression [16]. Distant recurrence was defined as the appearance of new tumors other than treated tumors [16]. Complications were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0 on the procedure number basis. Adverse events (AEs) of grade 3 or greater were defined as major complications; grade 2 AEs were defined as minor.
Int J Clin Oncol
Fig. 2 Retroperitoneal metastasis developed in the retroperitoneum 38 months after a 47-year-old man had undergone resection of chondrosarcoma in his thigh. a An axial contrast-enhanced CT image shows a recurrent tumor in the retroperitoneum (arrow). b Radiofrequency ablation (RFA) was performed after placing an RF electrode (white arrow) in the tumor under real-time CT fluoroscopic guidance.
Hydrodissection was performed before RFA in order to separate the bowel from the tumor by injecting distilled water mixed with contrast medium (asterisk) using an 18-gauge needle (black arrow). c Contrast-enhanced CT image shows disappearance of tumor enhancement 5 days after RFA. d The treated tumor had shrunk 6 months after RFA
Statistical analysis
analyses were performed using software (SAS, release 9.1; SAS Institute Inc., Cary, NC).
Cumulative overall survival curves beginning at the time of RFA were generated using the Kaplan–Meier method in September 2013. To identify significant prognostic factors, patients were divided into two subgroups based on the 12 factors presented in Table 2. Cumulative survival of each subgroup was compared using the log-rank test. Histology was not adopted as a variable because of the wide range of histology types. Patient and tumor backgrounds were compared between the patient group in which all tumors were ablated completely and that in which viable tumors remained after RFA using the Wilcoxon rank-sum test for continuous variables, and the Fisher’s exact and chi-squared tests for categorical variables. Multivariate analysis was performed using the Cox proportional hazard model. Data are expressed as mean ± standard deviation. A p value \0.05 was regarded as indicating statistical significance. All statistical
Results RFA and recurrences The mean follow-up period was 25.5 ± 24.2 months (range 3.9–117 months) in all patients. Treatment results are presented in Fig. 1. All initially targeted tumors were ablated completely in 21 patients (40.4 %, 21/52) after 42 RF sessions (1–5 sessions/patient). Of the 21 patients, 14 (66.7 %, 14/21) experienced rerecurrence after RFA: local tumor progression developed in 2 patients (9.5 %, 2/21), distant recurrence in 10 patients (47.6 %, 10/21), and both in 2 patients (9.5 %) (Table 1; Fig. 1). Ten of the14 patients (71.4 %) having re-recurrent tumors received RFA again (another 48 RF sessions). Of
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Int J Clin Oncol Table 3 Adverse events Grade
Incidence
Grade 5
0 (0 %)
Grade 4
0 (0 %)
Grade 3
2 (0.9 %)
Grade 2
68 (30.8 %)
Adverse events
Hemothorax (n = 1) Diaphragmatic herniation (n = 1) Pneumothorax (n = 58) Pain (n = 5) Decrease in hemoglobin level (n = 2) Subcutaneous emphysema (n = 2) Hemoptysis (n = 1)
Fig. 3 Overall survival curves in 52 patients. Overall survival rates were 73.4 % (95 % CI 61.0–85.9 %) at 1 year, 39.3 % (95 % CI 23.6–54.9 %) at 3 years, and 34.3 % (95 % CI 18.0–50.7 %) at 5 years
the remaining 4 patients, 2 received surgery for re-recurrent tumors, and 2 underwent no treatment because multiple tumors had appeared. Re-recurrent tumors were controlled again, after RFA in 7 patients and after surgical intervention in one. Therefore, 15 patients showed no evidence of disease at the last follow-up (28 %, 15/52) (Fig. 1). However, viable tumors remained even after 121 RF sessions (1–9 sessions/patient) were performed in 31 patients (59.6 %, 31/52). Because of the increase in tumor number during the treatment course in 30 of these patients, not all tumors were treated using RFA. In the remaining patient, although all mediastinal tumors were treated over 9 RF sessions, viable tumors remained at a site adjacent to the heart and pulmonary vessels. Of 31 patients with residual tumors, 18 underwent subsequent treatments such as chemotherapy, surgery, and radiotherapy. The other 13 patients received the best supportive care. None of those patients in whom complete tumor ablation was achieved by RFA experienced evidence of disease during the follow-up period. In total, 211 RF sessions were performed during the follow-up of all 52 patients. Differences in tumor number were found between the two patient groups, with and without complete tumor ablation (Table 1). Survival Twenty-eight patients (53.8 %, 28/52) had died of tumor progression by the end of follow-up. Overall survival rates were 73.4 % (95 % CI 61.0–85.9 %) at 1 year, 39.3 % (95 % CI 23.6–54.9 %) at 3 years, and 34.3 % (95 % CI 18.0–50.7 %) at 5 years in all patients (Fig. 3).
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Disease-free intervals of more than 2 years from the treatment of primary lesion (p = 0.040), tumor number of 3 or fewer (p = 0.0094), and complete tumor ablation (p \ 0.0001) were detected as significantly better prognostic factors in the univariate analysis (Table 2). The disease-free interval (p = 0.22, hazard ratio 0.24; 95 % CI 0.07–0.81) and complete tumor ablation (p = 0.0002; hazard ratio 0.30; 95 % CI 0.05–0.19) retained their significance in the Cox proportional hazard model. Complications There were no grade 5 (death) or grade 4 AE complications related to the RF procedures (Table 3). Grade 3 AEs occurred in 2 RF sessions (0.9 %, 2/221). Hemothorax requiring blood transfusion developed in one patient, and diaphragmatic herniation requiring surgical repair in one patient. Grade 2 AEs (minor complications) occurred after 68 of the RF sessions (30.8 %, 68/221). Pneumothorax requiring chest drainage was the most frequent minor complication.
Discussion These results show that RFA is a useful therapeutic option in selected patients with recurrent bone and soft-tissue sarcomas. Complete tumor ablation was detected as a significant prognostic factor. After surgical treatment, complete resection of all recurrent sarcomas is also known to be a prognostic factor [6, 17–23]. The post-recurrence 5-year survival rate (64.1 %) achieved in 21 patients in whom all tumors were ablated completely was almost equal to that following complete resection of all recurrent tumors. The post-surgical 5-year survival rate has been reported as 28–75 % [5, 6, 9, 19–23]. Given that both RFA and surgery are loco-regional treatments, it is reasonable that the same prognostic factors should be identified when all tumors are eradicated completely.
Int J Clin Oncol
Tumor number was also detected as a significant prognostic factor in univariate analysis. Guidelines suggest resection of limited metastases, in particular up to 2 or 3 lung metastases, to achieve long-term survival [1–3, 7, 8]. The fewer the tumors, the greater the possibility of achieving complete tumor ablation. A significant difference in tumor number was found between patient groups with and without complete tumor ablation. However, the median survival time (13.4 months) was almost identical to that after chemotherapy in 31 patients in whom viable tumors remained after RFA [3, 4, 11]. Because most of the patients who received RFA and then ended up with palliative treatment had disseminated diseases, and because few useful treatments other than RFA are available, the potential exists for them to receive some survival benefit from RFA. Comparison of RFA and best supportive care is necessary to confirm whether RFA is useful in prolonging the survival of patients with disseminated recurrent sarcomas. Given the frequent re-recurrence found in patients with recurrent bone and soft-tissue sarcomas, repeatability of RFA is clearly a benefit. It is noteworthy that more than 70 % of patients (10/21) with re-recurrence after complete tumor ablation underwent RFA again. Tumors were controlled again in 70 % (7/10) of those patients (Fig. 1). Another independent prognostic factor detected in this study was the disease-free interval. Previous studies have demonstrated the importance of the disease-free interval (1–2.5 years) in determining post-resection survival [23, 24]. The disease-free interval is regarded as an indication of the biological aggression of the tumor [23]. Complications found in this study have been reported previously [10]. The complication rates (major and minor complication rates of 0.9 and 30.8 %) following RFA are regarded as acceptable compared with those following resection of recurrent sarcomas (23–44 %) [9, 17, 19, 25]. The limitations of this study are its retrospective nature, inhomogeneous patients, and small size. Nevertheless, results derived from this study will help to identify those patients with recurrent bone and soft-tissue sarcoma who would benefit from RFA. In conclusion, RFA is a safe treatment for recurrent bone and soft-tissue sarcomas. Prognostic factors detected in this study will help to stratify patients and to identify those who would benefit most from RFA. Conflict of interest of interest.
The authors declare that they have no conflict
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2. NCCN Clinical Practice Guidelines in Oncology (2012) Bone Cancer. Version 2.2012. National Comprehensive Cancer Network, Inc., Fort Washington, PA 3. Grimer R, Judson I, Peake D et al (2010) Guidelines for the management of soft-tissue sarcomas. Sarcoma 2010:506182 4. Chou AJ, Merola PR, Wexler LH et al (2005) Treatment of osteosarcoma at first recurrence after contemporary therapy: The Memorial Sloan-Kettering Cancer Center experience. Cancer 104:2214–2221 5. Bacci G, Briccoli A, Longhi A et al (2005) Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol 44:748–755 6. Ferrari S, Briccoli A, Mercuri M (2003) Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival. J Clin Oncol 21:710–715 7. ESMO/European Sarcoma Network Working Group (2012) Softtissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Suppl 7:vii92– vii99 8. ESMO/European Sarcoma Network Working Group (2012) Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Suppl 7:vii100–vii109 9. Weber KL, Pring ME, Sim FH (2002) Treatment and outcome of recurrent pelvic chondrosarcoma. Clin Orthop Relat Res 397:19–28 10. Nakamura T, Matsumine A, Yamakado K et al (2009) Lung radiofrequency ablation in patients with pulmonary metastases from musculoskeletal sarcomas. Cancer 115:3774–3781 11. Antman K, Crowley J, Balcerzak SP et al (1993) An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft-tissue and bone sarcomas. J Clin Oncol 11:1276–1285 12. Keil S, Bruners P, Brehmer B et al (2008) Percutaneous radiofrequency ablation for treatment of recurrent retroperitoneal liposarcoma. Cardiovasc Intervent Radiol 31(Suppl 2):S213– S216 13. Nakamura T, Matsumine A, Yamakado K et al (2013) Clinical significance of radiofrequency ablation and metastasectomy in elderly patients with lung metastases from musculoskeletal sarcomas. J Cancer Res Ther 9(2):219–223 14. Takaki H, Nakatsuka A, Uraki J et al (2013) Renal cell carcinoma: radiofrequency ablation with a multiple-electrode switching system–a phase II clinical study. Radiology 267:285–292 15. Hasegawa T, Takaki H, Miyagi H et al (2013) Hyaluronic acid gel injection to prevent thermal injury of adjacent gastrointestinal tract during percutaneous liver radiofrequency ablation. Cardiovasc Intervent Radiol 36:1144–1146 16. Goldberg SN, Grassi CJ, Cardella JF et al (2009) Society of Interventional Radiology Technology Assessment Committee and the International Working Group on Image-guided Tumor Ablation. Image-guided tumor ablation: standardization of terminology and reporting criteria. J Vasc Interv Radiol 20:S377– S390 17. Lehnert T, Cardona S, Hinz U et al (2009) Primary and locally recurrent retroperitoneal soft-tissue sarcoma: local control and survival. Eur J Surg Oncol 35:986–993 18. Kim S, Ott HC, Wright CD et al (2011) Pulmonary resection of metastatic sarcoma: prognostic factors associated with improved outcomes. Ann Thorac Surg 92:1780–1786 19. Rehders A, Peiper M, Stoecklein NH et al (2009) Hepatic metastasectomy for soft-tissue sarcomas: is it justified? World J Surg 33:111–117 20. Lin PP, Alfawareh MD, Takeuchi A et al (2012) Sixty percent 10-year survival of patients with chondrosarcoma after local recurrence. Clin Orthop Relat Res 470:670–676
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ORIGINAL ARTICLE
Radiofrequency ablation for the treatment of recurrent bone and soft-tissue sarcomas in non-surgical candidates Koichiro Yamakado • Akihiko Matsumine • Tomoki Nakamura • Atsuhiro Nakatsuka Haruyuki Takaki • Takao Matsubara • Kunihiro Asanuma • Akihiro Sudo • Yoshiki Sugimura • Hajime Sakuma
•
Received: 25 September 2013 / Accepted: 4 November 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Aims The aim of this study was to evaluate the safety and clinical utility of radiofrequency ablation (RFA) retrospectively in non-surgical candidates with recurrent bone and soft-tissue sarcomas. Methods Percutaneous RFA was used in 52 patients (21 female, 31 male; mean age, 52.2 ± 21.1 years; range 10–87 years) with recurrent bone and soft-tissue sarcomas. The number of tumors was 3 or fewer in 23 patients (44.2 %) and 4 or more in the others, with a mean maximum tumor diameter of 3.0 ± 3.7 cm (range 0.5–18 cm). Safety, tumor control, and prognosis were evaluated. Results All tumors were ablated after RFA in 21 patients (40.4 %, 21/52), although 14 experienced re-recurrence. Tumors were controlled in 8 cases of recurrence by repeat RFA (n = 7) and surgical intervention (n = 1). Therefore, 15 patients (28.8 %, 15/52) were tumor-free at the end of follow-up (mean follow-up 25.5 ± 24.2 months; range 3.9–117 months). Residual tumors were found after RFA in
K. Yamakado (&) A. Nakatsuka H. Takaki Department of Interventional Radiology, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan e-mail: [email protected] A. Matsumine T. Nakamura T. Matsubara K. Asanuma A. Sudo Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Japan Y. Sugimura Department of Urology, Mie University School of Medicine, Tsu, Japan H. Sakuma Department of Diagnostic Radiology, Mie University School of Medicine, Tsu, Japan
the other 31 patients (59.6 %, 31/52). Overall survival rates were 73.4 % (95 % CI 61.0–85.9 %) at 1 year, 39.3 % (95 % CI 23.6–54.9 %) at 3 years, and 34.3 % (95 % CI 18.0–50.7 %) at 5 years in all patients. Recurrence-free interval (p = 0.040), tumor number (p = 0.0094), and complete tumor ablation (p \ 0.0001) were detected as significant prognostic factors in univariate analysis. The latter two factors were significant in multivariate analysis. The rate of major complications was 0.9 %. Conclusions RFA is a safe and useful therapeutic option for treatment of recurrent bone and soft-tissue sarcomas. Prognostic factors found in this study will help to identify those patients who would benefit from RFA. Keywords Bone sarcoma Soft tissue sarcoma Recurrence Radiofrequency ablation Prognosis
Introduction Sarcomas account for approximately 1 % of all adult malignancies and 15 % of pediatric malignancies [1]. Even after complete remission following the primary treatment, 30–35 % of bone sarcoma patients and about 50 % of soft-tissue sarcoma patients experience local or systemic relapse [2–6]. Although standard treatments for recurrent sarcomas have not been established, complete removal of all tumors irrespective of local or systemic recurrence is advocated to achieve long-term survival [1–3, 6–9]. Nevertheless, not all patients benefit from surgical treatment. Although the lung is the most frequent site for distant metastasis, only 25–30 % of patients with lung metastases benefit from metastasectomy because of the multiplicity of lung metastases, associated recurrences at other sites, and comorbid diseases [10].
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Systemic chemotherapy has minimal impact on the survival of most patients with recurrent sarcomas. Most patients die within 1 year, with a median survival time of 8.3–14.9 months after the diagnosis of recurrence [3, 4, 11]. Therefore, it is important to explore a new treatment strategy for recurrent sarcomas in non-surgical candidates. Although guidelines suggest the use of radiofrequency ablation (RFA) for the treatment of advanced sarcoma [1, 7], few reports have described its clinical utility in controlling recurrent sarcomas or its impact on patient prognosis [10, 12]. This study retrospectively evaluated the clinical utility of RFA in non-surgical candidates with recurrent bone and soft-tissue sarcomas.
Materials and methods Study design and patients Our institutional review board approved this study and waived the requirement for informed consent to use data
for research purposes. Informed consent to perform RFA was obtained appropriately from the patient or a parent before all treatments. Application of RFA for recurrent sarcomas was determined by discussion between surgeons, urologists, orthopedic surgeons, medical and radiation oncologists, and interventional radiologists. RFA was performed when tumors were considered unresectable, when there was a risk of causing severe complications after surgery, or when patients refused to undergo surgical intervention. We analyzed a prospectively collected computerized database. Between September 2000 and September 2012, 54 consecutive patients received RFA for the treatment of recurrent bone and soft-tissue sarcomas at our institution (Tables 1, 2; Fig. 1). Two patients were excluded from this study because the follow-up period was shorter than 6 months. 52 patients were included in this study. Twentyfive patients (48.1 %, 25/52) with lung metastases had been included in previous studies [10, 13]. All patients were judged as non-surgical candidates except one patient, a 10-year-old girl with recurrent neck tumor. She and her parents refused surgery for cosmetic reasons.
Table 1 Patient and tumor backgrounds Variables
All patients
Complete ablation group
Residual tumor group
p value
Number
52
21
31
Female/male
21/31
9/12
11/20
0.77
Age (years)
52.2 ± 21.1 (range 10–87)
51.9 ± 21.9 (range 10–87)
51.8 ± 22.2 (range 11–81)
0.78
B50 years/[50 years
22/30
9/12
11/20
0.77
Patient characteristics
Primary tumor Lower extremities/retroperitoneum/others
25/10/17
8/6/7
17/4/10
Bone/soft tissue
16/36
6/15
10/21
0.21
LMS/OS/LS/MFH/CS/Others
11/8/6/6/5/16
3/2/4/3/3/6
8/6/2/3/2/10
0.50
39.8 ± 39.8 (range 0–134)
36.1 ± 37.1 (range 2–125)
34.4 ± 39.2 (range 0–130)
0.061
30/22
11/10
19/12
0.58
25/27 23/29
10/11 7/14
15/16 16/15
[0.99 0.26
[0.99
Recurrent tumors Recurrence-free period (months) B2 years/[2 years Previous chemotherapy, yes/no Previous surgery, yes/no Involved organs
0.27
Lung
30
9
20
Lung and other organ
9
5
5
0.16 [0.99
Retroperitoneum
9
5
2
Body wall
2
2
2
[0.99
Mediastinum
2
0
2
0.51
Local recurrence/Metastasis
9/43
6/15
3/28
0.13
Maximum tumor diameter (cm)
3.0 ± 3.7 (range 0.5–18)
2.2 ± 1.6 (range 0.6–6.8)
3.5 ± 4.4 (range 0.5–18.0)
0.51
46/6
20/1
26/5
0.38
12/18/22
11/10/0
1/8/22
B5 cm/[5 cm
0.074
Tumor number Single/2–6/C 7
LMS leiomyosarcoma, OS osteosarcoma, LS liposarcoma, MFH malignant fibrous histiocytoma, CS chondrosarcoma
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\0.0001
Int J Clin Oncol Table 2 Overall survival rates based on variables
Patient number
Survival rate (%) 1-year
3-year
MST (months)
p value
5-year
Gender Female
20
75.6
42.0
42.0
28
Male
32
72.0
38.1
19.1
24.7
0.43
B50 years
22
76.6
49.1
40.9
35.7
[50 years
30
70.6
31
31
19.1
Lower extremities
25
52.4
37.5
37.5
17.8
Others
27
92.2
37.7
28.3
27.7
16 36
69 75.6
53.7 31.9
35.8 31.9
46.2 19.1
0.67
0.035
Age 0.51
Primary tumor location 0.49
Bone or soft tissue Bone Soft tissue Recurrence-free period B2 years
30
63.3
27.2
27.2
17.2
[2 years
22
90.2
60.2
48.2
46.2
Chemotherapy for recurrent tumor Yes
25
59.5
44.6
37.2
17.2
No
27
87.3
35
35
27.7
0.32
Surgery for recurrent tumor Yes
23
76
23.5
23.5
24.7
0.7
No
29
71.4
46.9
39.1
27.7
Lung alone
29
60.9
30.4
22.8
17.2
Others
23
91.1
53.2
53.2
68.8
9 43
100 68.2
55.6 35.2
55.6 29.3
68.8 18.3
0.13
0.44
Involved organs 0.1
Treated tumors Local recurrence Metastasis
Maximum tumor diameter (cm) B5
46
75
40.1
34.4
27.7
[5
6
53.3
26.7
26.7
15.6
B3
23
95.7
51.9
44.5
46.2
C4
29
54.8
32
32
15.6
64.1
68.8
Tumor number 0.019
Treatment results MST median survival time, NA not applicable
Curative
21
Palliative
31
The patients examined in this study were 20 females and 32 males with mean age of 52.2 ± 21.1 years (range 10–87 years). The primary tumors were bone sarcoma in 16 patients (30.8 %, 16/52) and soft-tissue sarcoma in the other 36 patients (36/52, 69.2 %). The histology varied as shown in Table 1. Pretreatment workup included brain, lung, abdomen, and pelvic computed tomography (CT) studies with and without contrast medium administration (Fig. 2a). When primary lesions were in extremities, images including the primary
100 53.6
73.2 15.3
NA
\0.0001
13.4
resected regions were acquired. The diagnosis of recurrent tumors was established by biopsy in 38 patients (73.1 %, 38/52), and by serial CT or magnetic resonance (MR) imaging studies in the other patients. New tumors that increased in size over time were regarded as recurrent sarcomas. Recurrent tumors were found within 2 years after the initial treatment in 30 patients (57.7 %, 30/52) and beyond 2 years in the other 22 patients (42.3 %, 22/52). The most frequent site of recurrence was the lung, found in 39 patients (75.0 %, 39/52). Local recurrence in the primary
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Int J Clin Oncol Fig. 1 Courses of treatment in patients who underwent radiofrequency ablation for recurrent bone and soft-tissue sarcoma. RFA radiofrequency ablation, Chemo chemotherapy, BSC best supportive care
tumor site was found in 9 patients (17.3 %, 9/52). The tumor number was single in 12 patients (23.1 %, 12/52), 2–6 in 18 patients (34.6 %), and 7 or more in the other 22 patients (42.3 %, 22/52). The mean maximum tumor diameter was 3.0 ± 3.7 cm (range 0.5–18 cm) at the time of initial RFA. RFA RFA was performed on an inpatient basis under general anesthesia in 2 children (10 and 12 years) and under local anesthesia in the 50 adult patients. Antibiotics (Cefazolin; Astellas Pharma Inc., Tokyo, Japan) were administered prophylactically before and for 1–2 days after RFA. Three interventional radiologists (KY, AN, HT) performed the RFA. Internally cooled RF electrodes (Cool-Tip RFA System; Valleylab, Boulder, CO, USA) were placed into each tumor based on the tumor size and shape under realtime CT fluoroscopic guidance (Aquilion; Toshiba Medical Systems Corp., Nasu, Japan) (Fig. 2b). After connecting the electrode to a generator (Series CC-1, RF 3000; Valleylab, Boulder, CO, USA), RF energy was applied for 12 min using an impedance-control algorithm. When target tumors were multiple, 2–3 tumors were treated per session. When the tumor was located adjacent to a critical organ, such as the bowel, distilled water (Otsuka Pharmaceutical,
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Tokyo, Japan) or hyaluronic acid gel (Adant, Meiji Seika Pharma Co. Ltd., Tokyo, Japan) was injected between the tumor and the critical organ in order to separate them (Fig. 2b) [14, 15]. CT or MR studies with and without contrast enhancement were performed within 1 week of RFA to evaluate the antitumor effects. Complete disappearance of tumor enhancement was regarded as complete tumor necrosis (Fig. 2c). When tumor enhancement remained after RFA, the RFA was repeated during the subsequent week provided repeat RFA was judged to be safe.
Follow-up and complications Physical examination and laboratory tests were performed every month. CT and MR studies were conducted with and without contrast enhancement every 3–4 months on an outpatient basis (Fig. 2c, d). Enlargement of an ablative tumor was regarded as local tumor progression [16]. Distant recurrence was defined as the appearance of new tumors other than treated tumors [16]. Complications were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0 on the procedure number basis. Adverse events (AEs) of grade 3 or greater were defined as major complications; grade 2 AEs were defined as minor.
Int J Clin Oncol
Fig. 2 Retroperitoneal metastasis developed in the retroperitoneum 38 months after a 47-year-old man had undergone resection of chondrosarcoma in his thigh. a An axial contrast-enhanced CT image shows a recurrent tumor in the retroperitoneum (arrow). b Radiofrequency ablation (RFA) was performed after placing an RF electrode (white arrow) in the tumor under real-time CT fluoroscopic guidance.
Hydrodissection was performed before RFA in order to separate the bowel from the tumor by injecting distilled water mixed with contrast medium (asterisk) using an 18-gauge needle (black arrow). c Contrast-enhanced CT image shows disappearance of tumor enhancement 5 days after RFA. d The treated tumor had shrunk 6 months after RFA
Statistical analysis
analyses were performed using software (SAS, release 9.1; SAS Institute Inc., Cary, NC).
Cumulative overall survival curves beginning at the time of RFA were generated using the Kaplan–Meier method in September 2013. To identify significant prognostic factors, patients were divided into two subgroups based on the 12 factors presented in Table 2. Cumulative survival of each subgroup was compared using the log-rank test. Histology was not adopted as a variable because of the wide range of histology types. Patient and tumor backgrounds were compared between the patient group in which all tumors were ablated completely and that in which viable tumors remained after RFA using the Wilcoxon rank-sum test for continuous variables, and the Fisher’s exact and chi-squared tests for categorical variables. Multivariate analysis was performed using the Cox proportional hazard model. Data are expressed as mean ± standard deviation. A p value \0.05 was regarded as indicating statistical significance. All statistical
Results RFA and recurrences The mean follow-up period was 25.5 ± 24.2 months (range 3.9–117 months) in all patients. Treatment results are presented in Fig. 1. All initially targeted tumors were ablated completely in 21 patients (40.4 %, 21/52) after 42 RF sessions (1–5 sessions/patient). Of the 21 patients, 14 (66.7 %, 14/21) experienced rerecurrence after RFA: local tumor progression developed in 2 patients (9.5 %, 2/21), distant recurrence in 10 patients (47.6 %, 10/21), and both in 2 patients (9.5 %) (Table 1; Fig. 1). Ten of the14 patients (71.4 %) having re-recurrent tumors received RFA again (another 48 RF sessions). Of
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Int J Clin Oncol Table 3 Adverse events Grade
Incidence
Grade 5
0 (0 %)
Grade 4
0 (0 %)
Grade 3
2 (0.9 %)
Grade 2
68 (30.8 %)
Adverse events
Hemothorax (n = 1) Diaphragmatic herniation (n = 1) Pneumothorax (n = 58) Pain (n = 5) Decrease in hemoglobin level (n = 2) Subcutaneous emphysema (n = 2) Hemoptysis (n = 1)
Fig. 3 Overall survival curves in 52 patients. Overall survival rates were 73.4 % (95 % CI 61.0–85.9 %) at 1 year, 39.3 % (95 % CI 23.6–54.9 %) at 3 years, and 34.3 % (95 % CI 18.0–50.7 %) at 5 years
the remaining 4 patients, 2 received surgery for re-recurrent tumors, and 2 underwent no treatment because multiple tumors had appeared. Re-recurrent tumors were controlled again, after RFA in 7 patients and after surgical intervention in one. Therefore, 15 patients showed no evidence of disease at the last follow-up (28 %, 15/52) (Fig. 1). However, viable tumors remained even after 121 RF sessions (1–9 sessions/patient) were performed in 31 patients (59.6 %, 31/52). Because of the increase in tumor number during the treatment course in 30 of these patients, not all tumors were treated using RFA. In the remaining patient, although all mediastinal tumors were treated over 9 RF sessions, viable tumors remained at a site adjacent to the heart and pulmonary vessels. Of 31 patients with residual tumors, 18 underwent subsequent treatments such as chemotherapy, surgery, and radiotherapy. The other 13 patients received the best supportive care. None of those patients in whom complete tumor ablation was achieved by RFA experienced evidence of disease during the follow-up period. In total, 211 RF sessions were performed during the follow-up of all 52 patients. Differences in tumor number were found between the two patient groups, with and without complete tumor ablation (Table 1). Survival Twenty-eight patients (53.8 %, 28/52) had died of tumor progression by the end of follow-up. Overall survival rates were 73.4 % (95 % CI 61.0–85.9 %) at 1 year, 39.3 % (95 % CI 23.6–54.9 %) at 3 years, and 34.3 % (95 % CI 18.0–50.7 %) at 5 years in all patients (Fig. 3).
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Disease-free intervals of more than 2 years from the treatment of primary lesion (p = 0.040), tumor number of 3 or fewer (p = 0.0094), and complete tumor ablation (p \ 0.0001) were detected as significantly better prognostic factors in the univariate analysis (Table 2). The disease-free interval (p = 0.22, hazard ratio 0.24; 95 % CI 0.07–0.81) and complete tumor ablation (p = 0.0002; hazard ratio 0.30; 95 % CI 0.05–0.19) retained their significance in the Cox proportional hazard model. Complications There were no grade 5 (death) or grade 4 AE complications related to the RF procedures (Table 3). Grade 3 AEs occurred in 2 RF sessions (0.9 %, 2/221). Hemothorax requiring blood transfusion developed in one patient, and diaphragmatic herniation requiring surgical repair in one patient. Grade 2 AEs (minor complications) occurred after 68 of the RF sessions (30.8 %, 68/221). Pneumothorax requiring chest drainage was the most frequent minor complication.
Discussion These results show that RFA is a useful therapeutic option in selected patients with recurrent bone and soft-tissue sarcomas. Complete tumor ablation was detected as a significant prognostic factor. After surgical treatment, complete resection of all recurrent sarcomas is also known to be a prognostic factor [6, 17–23]. The post-recurrence 5-year survival rate (64.1 %) achieved in 21 patients in whom all tumors were ablated completely was almost equal to that following complete resection of all recurrent tumors. The post-surgical 5-year survival rate has been reported as 28–75 % [5, 6, 9, 19–23]. Given that both RFA and surgery are loco-regional treatments, it is reasonable that the same prognostic factors should be identified when all tumors are eradicated completely.
Int J Clin Oncol
Tumor number was also detected as a significant prognostic factor in univariate analysis. Guidelines suggest resection of limited metastases, in particular up to 2 or 3 lung metastases, to achieve long-term survival [1–3, 7, 8]. The fewer the tumors, the greater the possibility of achieving complete tumor ablation. A significant difference in tumor number was found between patient groups with and without complete tumor ablation. However, the median survival time (13.4 months) was almost identical to that after chemotherapy in 31 patients in whom viable tumors remained after RFA [3, 4, 11]. Because most of the patients who received RFA and then ended up with palliative treatment had disseminated diseases, and because few useful treatments other than RFA are available, the potential exists for them to receive some survival benefit from RFA. Comparison of RFA and best supportive care is necessary to confirm whether RFA is useful in prolonging the survival of patients with disseminated recurrent sarcomas. Given the frequent re-recurrence found in patients with recurrent bone and soft-tissue sarcomas, repeatability of RFA is clearly a benefit. It is noteworthy that more than 70 % of patients (10/21) with re-recurrence after complete tumor ablation underwent RFA again. Tumors were controlled again in 70 % (7/10) of those patients (Fig. 1). Another independent prognostic factor detected in this study was the disease-free interval. Previous studies have demonstrated the importance of the disease-free interval (1–2.5 years) in determining post-resection survival [23, 24]. The disease-free interval is regarded as an indication of the biological aggression of the tumor [23]. Complications found in this study have been reported previously [10]. The complication rates (major and minor complication rates of 0.9 and 30.8 %) following RFA are regarded as acceptable compared with those following resection of recurrent sarcomas (23–44 %) [9, 17, 19, 25]. The limitations of this study are its retrospective nature, inhomogeneous patients, and small size. Nevertheless, results derived from this study will help to identify those patients with recurrent bone and soft-tissue sarcoma who would benefit from RFA. In conclusion, RFA is a safe treatment for recurrent bone and soft-tissue sarcomas. Prognostic factors detected in this study will help to stratify patients and to identify those who would benefit most from RFA. Conflict of interest of interest.
The authors declare that they have no conflict
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