Clin Transl Oncol (2015) 17:668–672 DOI 10.1007/s12094-015-1291-1
BRIEF RESEARCH ARTICLE
Lung metastases in oligometastatic patients: outcome with stereotactic body radiation therapy (SBRT) S. Garcı´a-Cabezas1 • C. Bueno1 • E. Rivin2 • J. M. Rolda´n3 • A. Palacios-Eito1
Received: 19 March 2015 / Accepted: 10 April 2015 / Published online: 29 May 2015 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2015
Abstract Purpose To assess the clinical results in terms of local control, toxicity, failure pattern and toxicity of SBRT in oligometastatic patients with inoperable lung metastases. Methods Forty-four patients were treated (53 metastases). Dose regimen: 5 9 12 Gy (66 %), 8 9 7.5 Gy (20.8 %) and 10 9 5 Gy (13.2 %). Response was assessed using PET/CT at 6 months after SBRT. Results Local control at 1 and 2 years was 86.7 %. Seventy-five percent of local failures had received a BED \105 Gy. After a median follow-up of 13.3 months, 25 % experienced distant progression. Overall survival at 1 and 2 years was 86.7 and 60.4 %, and cancer-specific survival was 95.3 and 75.2 %, respectively. Grade 2 toxicity was 6.8 %. There was no grade 3–4 toxicity. Conclusion SBRT is effective and safe. The main failure pattern is distant progression. The selection of patients with a high probability of remaining oligometastatic is crucial for the efficiency of SBRT, both clinically and in terms of resources.
& A. Palacios-Eito [email protected] S. Garcı´a-Cabezas [email protected] 1
Department of Radiation Oncology, Reina Sofı´a University Hospital, Avda. Mene´ndez Pidal, s/n, 14004 Co´rdoba, Spain
2
Department of Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France
3
Department of Medical Physics, Reina Sofia University Hospital, Cordoba, Spain
123
Keywords Lung metastases SBRT Stereotactic radiotherapy Oligometastases
Introduction Treatment of metastatic disease has been mainly based on systemic approaches. The notion of an oligometastatic state, as initially described in 1995 by Hellman and Weichselbaum [1], led to the hypothesis that these patients may opt for treatments with curative intent through local ablation procedures. This hypothesis has been confirmed by surgery, particularly in the case of lung metastasis resection [2]. However, a subset of these patients is not amenable to surgery for either clinical or technical reasons. Limited toxicity, good clinical results, and the experience gained using SBRT in stage I NSCLC have led to the use of this technique in lung metastases. Prospective phase I/II studies have shown that SBRT is safe and effective as treatment of lung metastases [3, 4], and several institutions have published their results in this regard [4–11]. SBRT of inoperable lung metastases is today considered routine in clinical practice, but its implementation varies widely in different centers due to the technical infrastructure it requires [12]. The primary objective of this retrospective analysis was to determine the clinical results of this treatment performed with potentially curative intent in terms of local control (LC), failure pattern and toxicity. Secondary analyses included the difficulty to quantify local response, overall survival (OS), progression-free survival (PFS) and cancer-specific survival (CSS) obtained with SBRT in multitreated, inoperable lung oligometastatic patients.
Clin Transl Oncol (2015) 17:668–672
Materials and methods
669 Table 1 Patient and treatment characteristics Characteristic
Between May 2011 and October 2014, 44 consecutive patients received SBRT treatment for 53 lung lesions. Inclusion criteria were oligometastatic disease: B5 metastases, up to 5 cm in size by computed tomography (CT) imaging, of any histology, with controlled primary tumor, with no surgical options and a Karnofsky Index C70. The fractionations used were 5 9 12 Gy (BED [10, 13] 2 Gy) for peripheral lesions while 8 9 7.5 Gy (BED [10] 5 Gy) or 10 9 5 Gy (BED [10] 0 Gy) to central lesions. Delineation of the Internal Tumor Volume (ITV) was based on a 4D-CT. Organ-at-risk dosing limits were according to AAPM recommendations [13]. Image acquisition and irradiation were performed with abdominal compression for respiratory control, and irradiation was by volumetric modulated arc therapy technique with an Elekta Synergy LINAC with a multileaf collimator (modulating beam) and image guidance. Coverage obtained for the PTV was V95 % [95 % of the prescribed dose and V98 % [98 % for the ITV. The PTV was obtained after a 3-mm isotropic expansion of the ITV. Response was established according to PET/CT imaging (PERCIST criteria) at 6 months after the end of SBRT and compared to response by CT (RECIST criteria) at 3 months after treatment completion. LC was defined as the absence of progression in the treatment volume assessed by PET/CT. Toxicity was assessed according to the NCI CTCAE v3.0 scale. LC and survival were measured using the Kaplan–Meier method from the time of SBRT initiation. Results were compared using the log-rank test. A p value\0.05 was considered statistically significant. SPSS 17 was used for analyses.
Results
N (%)
Patient and treatment characteristics Num. of patients
44
Num. of lesions
53
Age (years) Median
74
Range
(50–86)
Gender Female
6 (13.6 %)
Male
38 (86.4 %)
KI 70 80
10 (22.7 %) 15 (34.1 %)
90
19 (43.2 %)
Primary tumor Colorectal
20 (45.4 %)
Lung
10 (22.7 %)
Head and neck
6 (13.6 %)
Renal carcinoma
4 (9.1 %)
Breast
2 (4.5 %)
Endometrial
1 (2.3 %)
Thyroid
1 (2.3 %)
Histological type Adenocarcinoma
24 (54.5 %)
Squamous Cell
20 (45.4 %)
Initially metastatic Yes
8 (18.2 %)
No 36 (81.8 %) Num. of lung lesions treated per patient with SBRT 1
36 (81.8 %)
2
7 (15.9 %)
3
1 (2.3 %)
Previous chemotherapy
Fifty-three lung lesions were treated in 44 patients. Patient characteristics are described in Table 1. Ninety-one percent of patients had PET/CT and CT before starting treatment and only 9 % had CT. The median follow-up was 13.3 months (range 3.6–46.2). Table 2 shows the response to treatment and the difference between CT and PET/CT images. Agreement for both response assessments was 38.7 %. No G3-4 toxicity occurred. In one patient, an asymptomatic rib fracture was identified (G1) and three patients had G2 (6, 8 %) lung toxicity requiring corticosteroid therapy. The rate of local control at 1 and 2 years was 86.7 %. The different LC rates associated with the factors histology, size and BED are expressed in Table 3. Significant differences were only observed for the size factor. Median survival was 34 months (27.9–40.3). At the time of analysis, 34 patients (77.3 %) were alive and 10
Yes
27 (61.4 %)
No
17 (38.6 %)
Previous radiotherapy Yes
14 (31.8 %)
No
30 (68.2 %)
Previous surgery Yes
27 (61.4 %)
No
17 (38.6 %)
Extrathoracic metastatic disease Yes No
5 (11.4 %) 39 (88.6 %)
ITV (cm3) Median
12.9
Range
(1.47–52)
Maximum dimension (mm) Median
20
123
670
Clin Transl Oncol (2015) 17:668–672
Table 1 continued Characteristic
N (%)
Range
5–45
Dose prescription per lesion (Gy/fraction) 5 9 12 Gy
35 (66 %)
8 9 7.5 Gy
11 (20.8 %)
10 9 5 Gy
7 (13.2 %)
Table 2 Comparison and difference between treatment response appreciated by CT and PET/CT at 3 and 6 months after SBRT Recist (3 months) (%)
Percist (6 months) (%)
12.9
54.8
PR
51.6
25.8
-25.8
SD LP
25.8 9.7
6.5 12.9
-19.3 3.2
CR
Difference (%) 41.9
CR Complete response, PR partial response, SD stable disease and LP local Progression
(22.7 %) had died, 5 for reasons unrelated to disease. OS at 1 and 2 years was 86.7 and 60.4 % respectively, and CSS was 95.3 and 75.2 %. Regarding the progression pattern, fifteen patients (34 %) progressed (9 % locally and 25 % distantly). PFS at 1 and 2 years was 63.9 and 51.5 %. In patients who progressed, chemotherapy was prescribed in 46.6 %. At 4 months after SBRT completion, 42 % of patients maintained oligometastatic status. The median time from diagnosis to start of SBRT treatment was 22.6 months.
Discussion The primary objective of radiotherapy is to achieve LC. However, this achievement has no impact on survival if distant progression is not controlled or prevented.
The rates of local control reported using SBRT are in the range of 70–90 % at 2 years (Table 4). These rates are similar to those obtained after metastasectomy [2]. Our series is within the expected range, with LC rates at 1 and 2 years of 86.7 %. There are few large series, and most include patients with highly diverse histologies and different dose ranges. Several authors have associated LC with the size of metastasis (worse if [2.5 cm) [14], histology (unfavorable if not adenocarcinoma [15]) and the dose administered. We have found a significant association with tumor size C2.5 cm, but not with histology nor with the range of dose. This lack of association may be due to the low number of local recurrences, since based on the experience acquired in NSCLC, it is well known that a BED10 C100 Gy to the isocenter is required to achieve adequate LC [16]. For SBRT in lung metastases, the BED10 in the different series reported was 70–162 Gy. Such diversity in dose fractioning schemes means there is no consensus on the standard dose. Assessment of response after SBRT in the lung is a known challenge. Even in documented cases of CR, in 33 % the radiographic image by CT does not allow distinction of fibrosis from relapse [17]. In our series, the detection of CR increased by 41.9 % when assessment was performed by PET/CT. Two arguments may be put forward on the basis of these facts: Response to SBRT is slow and/ or assessment of response with RECIST criteria may be inadequate. Without biological information, it is difficult to differentiate tumor from fibrotic/necrotic changes secondary to SBRT. Persistence of a mild activity in PET/CT has been reported for long periods after treatment. This probably reflects the delayed inflammatory activity secondary to the administration of high doses per fraction and has not been associated with relapse. Although these findings require more investigation, PET/CT should be part of routine monitoring of patients undergoing SBRT [18]. Limited toxicity has been described for these treatments. It is reported to be \3 %, which may rise to 9 % in
Table 3 Analysis of factors affecting the local control rate, distant progression and overall survival Variables
Local control rate
p value*
Distant progression (%)
p value*
OS (%)
p value*
95
ns
25
ns
80
ns
Histology SQ AD Size of tumor
87.5
\2.5 cm
100
C2.5 cm
78.9
25 0.023
36
75 ns
10.2
72
ns
84.2
BED \105
80
C105
92.3
ns
SQ Squamous cell carcinoma, AD adenocarcinoma * v2 test
123
40 23.1
ns
100 74.4
ns
Clin Transl Oncol (2015) 17:668–672
671
Table 4 Summary of selected series of SBRT for lung metastases References
N
Total dose (Gy)
Median follow (mo)
Local control
OS
Okunieff et al. [3]
30
50–55
18.7
91 % (3 years)
38 % (2 years)
Norihisa et al. [6]
34
48–60
27.0
90 % (2 years)
84.3 % (2 years)
Rusthoven et al. [4]
63
48–60
15.4
96 % (2 years)
39 % (2 years)
Zhang et al. [7]
71
30–60
24.7
75.4 % (3 years)
40.8 % (3 years)
Ricardi et al. [8]
61
26–45
20.4
89 % (2 years)
66.5 % (2 years)
Baschnegel et al. [9]
47
48–60
27.6
85 % (3 years)
63 % (3 years)
Singh et al. [11]
34
40–60
16.7
88 % (2 years)
44 % (2 years)
Our series
53
50–60
13.3
86.7 (2 years)
60.4 (2 years)
centrally located lesions, and with a mortality risk \1 % [19]. It is common to observe subclinical radiological pneumonitis (G1) in imaging tests after treatment. Toxicity in this cohort was detected in 6.8 % (G2) of the cases. This low toxicity is associated with the strict compliance with limiting doses to healthy organs [13] and reduction of the prescribed dose (8 9 7.5 Gy) to centrally located tumors, to minimize the risk of bronchial stenosis/bleeding. The international registry of lung metastases treated by surgical excision published survival rates at 2, 5, and 10 years of 70, 36, and 26 %, respectively [2]. The OS at 2 years reported in larger series treated with SBRT ranges from 84 % reported by Norihisa [6] to 39 % in a multiinstitutional study [4]. OS at 1 and 2 years in our cohort was 86.7 and 60.4 % respectively. These values are within the range reported in the literature. In oligometastatic disease, it is very difficult to compare survival results between different series. The inclusion of multiple histologies, of patients with varied metastatic tumor burden, and with highly diverse prognoses (due to the underlying oncological disease) is common, in addition to different doses and techniques. Patients included in these series are also noncomparable to those which include surgical patients, because they are inoperable. Survival in our series may be associated with the inclusion of the first patients recruited at the institution. Included patients, even after multiple treatments, presented a long period between the primary diagnosis and start of SBRT (median of 22.6 months). This may indirectly lead to selecting patients with a strong tendency to be oligometastatic, as reflected by the results in terms of survival. The primary route of progression of these patients was distant progression, accounting for 25 % in our series. The current definition of an oligometastatic patient is based exclusively on clinical parameters. We need more precise biological parameters to identify this group of patients, since it is the subgroup in which reinforcing LC should improve survival. Preliminary surveys have identified a miRNA family [20] that will probably allow us to have a genomic test in the near future that objectively identifies
patients with a high probability of remaining oligometastatic over long time periods. In conclusion this study shows that SBRT is effective and safe for the treatment of lung metastases. The main failure pattern is distant progression. Randomized trials are required to quantify the impact of SBRT embedded early in systemic treatment on survival. The main, urgent goal is to identify patients with a high probability of maintaining oligometastatic status over long periods to concentrate all clinical efforts and resources on them. Conflict of interest
None.
Ethical standard The design and methodology of this study has been approved by the Ethics Committee of the Reina Sofia University Hospital of Cordoba. Informed consent
Informed consent was required.
References 1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1): 8–10. 2. Pastorino U, Buyse M, Friedel G, Ginsberg R, Girard P, Goldstraw P et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. The International Registry of Lung Metastases. J Thorac Cardiovasc Surg. 1997;113(1):37–49. 3. Okunieff P, Petersen AL, Philip A, Milano MT, Katz AW, Boros L, et al. Stereotactic body radiation therapy (SBRT) for lung metastases. Acta Oncol. 2006;45(7):808–17. doi:10.1080/02841860600908954. 4. Rusthoven KE, Kavanagh BD, Burri SH, Chen C, Cardenes H, Chidel MA, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol. 2009;27(10):1579–84. doi:10.1200/JCO.2008.19. 6386. 5. Siva S, MacManus M, Ball D. Stereotactic radiotherapy for pulmonary oligometastases: a systematic review. J Thorac Oncol. 2010;5(7):1091–9. doi:10.1097/JTO.0b013e3181de7143. 6. Norihisa Y, Nagata Y, Takayama K, Matsuo Y, Sakamoto T, Sakamoto M, et al. Stereotactic body radiotherapy for oligometastatic lung tumors. Int J Radiat Oncol Biol Phys. 2008;72(2):398–403. doi:10.1016/j.ijrobp.2008.01.002. 7. Zhang Y, Xiao JP, Zhang HZ, Yin WB, Hu YM. Stereotactic body radiation therapy favors long-term overall survival in patients with lung metastases: fiveyear experience of a single-institution. Med J Beijing. 2011. doi:10.3760/cma.j. issn.0366-6999.2011.24.003. 8. Ricardi U, Filippi AR, Guarneri A, Ragona R, Mantovani C, Giglioli F, et al. Stereotactic body radiation therapy for lung metastases. Lung Cancer. 2011;75(1):77–81. doi:10.1016/j.lungcan.2011.04.021. 9. Baschnagel AM, Mangona VS, Robertson JM, Welsh RJ, Kestin LL, Grills IS. Lung metastases treated with image-guided stereotactic body radiation therapy. Clin Oncol. 2013;25(4):236–41. doi:10.1016/j.clon.2012.12.005.
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672 10. Navarria P, Ascolese AM, Tomatis S, Cozzi L, De Rose F, Mancosu P, et al. Stereotactic body radiotherapy (sbrt) in lung oligometastatic patients: role of local treatments. Radiat Oncol. 2014;9(1):91. doi:10.1186/1748-717X-9-91. 11. Singh D, Chen Y, Hare MZ, Usuki KY, Zhang H, Lundquist T, et al. Local control rates with five-fraction stereotactic body radiotherapy for oligometastatic cancer to the lung. J Thoracic Dis. 2014;6(4):369–74. doi:10. 3978/j.issn.2072-1439.2013.12.03. 12. Buyyounouski MK, Balter P, Lewis B, D’Ambrosio DJ, Dilling TJ, Miller RC et al. Stereotactic body radiotherapy for early-stage non-small-cell lung cancer: report of the ASTRO Emerging Technology Committee. Radiat Oncol Biol. 2010;78(1):3–10. doi:10.1016/j.ijrobp.2010.04.010. 13. Benedict SH, Yenice KM, Followill D, Galvin JM, Hinson W, Kavanagh B, et al. Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys. 2010;37(8):4078–101. 14. Kim H, Ahn YC, Park HC, Lim DH, Nam H. Results and prognostic factors of hypofractionated stereotactic radiation therapy for primary or metastatic lung cancer. J Thorac Oncol. 2010;5(4):526–32. doi:10.1097/JTO.0b013e3181cbf622. 15. de Vin T, Engels B, Gevaert T, Storme G, de Ridder M. Stereotactic radiotherapy for oligometastatic cancer: a prognostic model for survival. Ann Oncol. 2014;25(2):467–71. doi:10.1093/annonc/mdt537.
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BRIEF RESEARCH ARTICLE
Lung metastases in oligometastatic patients: outcome with stereotactic body radiation therapy (SBRT) S. Garcı´a-Cabezas1 • C. Bueno1 • E. Rivin2 • J. M. Rolda´n3 • A. Palacios-Eito1
Received: 19 March 2015 / Accepted: 10 April 2015 / Published online: 29 May 2015 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2015
Abstract Purpose To assess the clinical results in terms of local control, toxicity, failure pattern and toxicity of SBRT in oligometastatic patients with inoperable lung metastases. Methods Forty-four patients were treated (53 metastases). Dose regimen: 5 9 12 Gy (66 %), 8 9 7.5 Gy (20.8 %) and 10 9 5 Gy (13.2 %). Response was assessed using PET/CT at 6 months after SBRT. Results Local control at 1 and 2 years was 86.7 %. Seventy-five percent of local failures had received a BED \105 Gy. After a median follow-up of 13.3 months, 25 % experienced distant progression. Overall survival at 1 and 2 years was 86.7 and 60.4 %, and cancer-specific survival was 95.3 and 75.2 %, respectively. Grade 2 toxicity was 6.8 %. There was no grade 3–4 toxicity. Conclusion SBRT is effective and safe. The main failure pattern is distant progression. The selection of patients with a high probability of remaining oligometastatic is crucial for the efficiency of SBRT, both clinically and in terms of resources.
& A. Palacios-Eito [email protected] S. Garcı´a-Cabezas [email protected] 1
Department of Radiation Oncology, Reina Sofı´a University Hospital, Avda. Mene´ndez Pidal, s/n, 14004 Co´rdoba, Spain
2
Department of Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France
3
Department of Medical Physics, Reina Sofia University Hospital, Cordoba, Spain
123
Keywords Lung metastases SBRT Stereotactic radiotherapy Oligometastases
Introduction Treatment of metastatic disease has been mainly based on systemic approaches. The notion of an oligometastatic state, as initially described in 1995 by Hellman and Weichselbaum [1], led to the hypothesis that these patients may opt for treatments with curative intent through local ablation procedures. This hypothesis has been confirmed by surgery, particularly in the case of lung metastasis resection [2]. However, a subset of these patients is not amenable to surgery for either clinical or technical reasons. Limited toxicity, good clinical results, and the experience gained using SBRT in stage I NSCLC have led to the use of this technique in lung metastases. Prospective phase I/II studies have shown that SBRT is safe and effective as treatment of lung metastases [3, 4], and several institutions have published their results in this regard [4–11]. SBRT of inoperable lung metastases is today considered routine in clinical practice, but its implementation varies widely in different centers due to the technical infrastructure it requires [12]. The primary objective of this retrospective analysis was to determine the clinical results of this treatment performed with potentially curative intent in terms of local control (LC), failure pattern and toxicity. Secondary analyses included the difficulty to quantify local response, overall survival (OS), progression-free survival (PFS) and cancer-specific survival (CSS) obtained with SBRT in multitreated, inoperable lung oligometastatic patients.
Clin Transl Oncol (2015) 17:668–672
Materials and methods
669 Table 1 Patient and treatment characteristics Characteristic
Between May 2011 and October 2014, 44 consecutive patients received SBRT treatment for 53 lung lesions. Inclusion criteria were oligometastatic disease: B5 metastases, up to 5 cm in size by computed tomography (CT) imaging, of any histology, with controlled primary tumor, with no surgical options and a Karnofsky Index C70. The fractionations used were 5 9 12 Gy (BED [10, 13] 2 Gy) for peripheral lesions while 8 9 7.5 Gy (BED [10] 5 Gy) or 10 9 5 Gy (BED [10] 0 Gy) to central lesions. Delineation of the Internal Tumor Volume (ITV) was based on a 4D-CT. Organ-at-risk dosing limits were according to AAPM recommendations [13]. Image acquisition and irradiation were performed with abdominal compression for respiratory control, and irradiation was by volumetric modulated arc therapy technique with an Elekta Synergy LINAC with a multileaf collimator (modulating beam) and image guidance. Coverage obtained for the PTV was V95 % [95 % of the prescribed dose and V98 % [98 % for the ITV. The PTV was obtained after a 3-mm isotropic expansion of the ITV. Response was established according to PET/CT imaging (PERCIST criteria) at 6 months after the end of SBRT and compared to response by CT (RECIST criteria) at 3 months after treatment completion. LC was defined as the absence of progression in the treatment volume assessed by PET/CT. Toxicity was assessed according to the NCI CTCAE v3.0 scale. LC and survival were measured using the Kaplan–Meier method from the time of SBRT initiation. Results were compared using the log-rank test. A p value\0.05 was considered statistically significant. SPSS 17 was used for analyses.
Results
N (%)
Patient and treatment characteristics Num. of patients
44
Num. of lesions
53
Age (years) Median
74
Range
(50–86)
Gender Female
6 (13.6 %)
Male
38 (86.4 %)
KI 70 80
10 (22.7 %) 15 (34.1 %)
90
19 (43.2 %)
Primary tumor Colorectal
20 (45.4 %)
Lung
10 (22.7 %)
Head and neck
6 (13.6 %)
Renal carcinoma
4 (9.1 %)
Breast
2 (4.5 %)
Endometrial
1 (2.3 %)
Thyroid
1 (2.3 %)
Histological type Adenocarcinoma
24 (54.5 %)
Squamous Cell
20 (45.4 %)
Initially metastatic Yes
8 (18.2 %)
No 36 (81.8 %) Num. of lung lesions treated per patient with SBRT 1
36 (81.8 %)
2
7 (15.9 %)
3
1 (2.3 %)
Previous chemotherapy
Fifty-three lung lesions were treated in 44 patients. Patient characteristics are described in Table 1. Ninety-one percent of patients had PET/CT and CT before starting treatment and only 9 % had CT. The median follow-up was 13.3 months (range 3.6–46.2). Table 2 shows the response to treatment and the difference between CT and PET/CT images. Agreement for both response assessments was 38.7 %. No G3-4 toxicity occurred. In one patient, an asymptomatic rib fracture was identified (G1) and three patients had G2 (6, 8 %) lung toxicity requiring corticosteroid therapy. The rate of local control at 1 and 2 years was 86.7 %. The different LC rates associated with the factors histology, size and BED are expressed in Table 3. Significant differences were only observed for the size factor. Median survival was 34 months (27.9–40.3). At the time of analysis, 34 patients (77.3 %) were alive and 10
Yes
27 (61.4 %)
No
17 (38.6 %)
Previous radiotherapy Yes
14 (31.8 %)
No
30 (68.2 %)
Previous surgery Yes
27 (61.4 %)
No
17 (38.6 %)
Extrathoracic metastatic disease Yes No
5 (11.4 %) 39 (88.6 %)
ITV (cm3) Median
12.9
Range
(1.47–52)
Maximum dimension (mm) Median
20
123
670
Clin Transl Oncol (2015) 17:668–672
Table 1 continued Characteristic
N (%)
Range
5–45
Dose prescription per lesion (Gy/fraction) 5 9 12 Gy
35 (66 %)
8 9 7.5 Gy
11 (20.8 %)
10 9 5 Gy
7 (13.2 %)
Table 2 Comparison and difference between treatment response appreciated by CT and PET/CT at 3 and 6 months after SBRT Recist (3 months) (%)
Percist (6 months) (%)
12.9
54.8
PR
51.6
25.8
-25.8
SD LP
25.8 9.7
6.5 12.9
-19.3 3.2
CR
Difference (%) 41.9
CR Complete response, PR partial response, SD stable disease and LP local Progression
(22.7 %) had died, 5 for reasons unrelated to disease. OS at 1 and 2 years was 86.7 and 60.4 % respectively, and CSS was 95.3 and 75.2 %. Regarding the progression pattern, fifteen patients (34 %) progressed (9 % locally and 25 % distantly). PFS at 1 and 2 years was 63.9 and 51.5 %. In patients who progressed, chemotherapy was prescribed in 46.6 %. At 4 months after SBRT completion, 42 % of patients maintained oligometastatic status. The median time from diagnosis to start of SBRT treatment was 22.6 months.
Discussion The primary objective of radiotherapy is to achieve LC. However, this achievement has no impact on survival if distant progression is not controlled or prevented.
The rates of local control reported using SBRT are in the range of 70–90 % at 2 years (Table 4). These rates are similar to those obtained after metastasectomy [2]. Our series is within the expected range, with LC rates at 1 and 2 years of 86.7 %. There are few large series, and most include patients with highly diverse histologies and different dose ranges. Several authors have associated LC with the size of metastasis (worse if [2.5 cm) [14], histology (unfavorable if not adenocarcinoma [15]) and the dose administered. We have found a significant association with tumor size C2.5 cm, but not with histology nor with the range of dose. This lack of association may be due to the low number of local recurrences, since based on the experience acquired in NSCLC, it is well known that a BED10 C100 Gy to the isocenter is required to achieve adequate LC [16]. For SBRT in lung metastases, the BED10 in the different series reported was 70–162 Gy. Such diversity in dose fractioning schemes means there is no consensus on the standard dose. Assessment of response after SBRT in the lung is a known challenge. Even in documented cases of CR, in 33 % the radiographic image by CT does not allow distinction of fibrosis from relapse [17]. In our series, the detection of CR increased by 41.9 % when assessment was performed by PET/CT. Two arguments may be put forward on the basis of these facts: Response to SBRT is slow and/ or assessment of response with RECIST criteria may be inadequate. Without biological information, it is difficult to differentiate tumor from fibrotic/necrotic changes secondary to SBRT. Persistence of a mild activity in PET/CT has been reported for long periods after treatment. This probably reflects the delayed inflammatory activity secondary to the administration of high doses per fraction and has not been associated with relapse. Although these findings require more investigation, PET/CT should be part of routine monitoring of patients undergoing SBRT [18]. Limited toxicity has been described for these treatments. It is reported to be \3 %, which may rise to 9 % in
Table 3 Analysis of factors affecting the local control rate, distant progression and overall survival Variables
Local control rate
p value*
Distant progression (%)
p value*
OS (%)
p value*
95
ns
25
ns
80
ns
Histology SQ AD Size of tumor
87.5
\2.5 cm
100
C2.5 cm
78.9
25 0.023
36
75 ns
10.2
72
ns
84.2
BED \105
80
C105
92.3
ns
SQ Squamous cell carcinoma, AD adenocarcinoma * v2 test
123
40 23.1
ns
100 74.4
ns
Clin Transl Oncol (2015) 17:668–672
671
Table 4 Summary of selected series of SBRT for lung metastases References
N
Total dose (Gy)
Median follow (mo)
Local control
OS
Okunieff et al. [3]
30
50–55
18.7
91 % (3 years)
38 % (2 years)
Norihisa et al. [6]
34
48–60
27.0
90 % (2 years)
84.3 % (2 years)
Rusthoven et al. [4]
63
48–60
15.4
96 % (2 years)
39 % (2 years)
Zhang et al. [7]
71
30–60
24.7
75.4 % (3 years)
40.8 % (3 years)
Ricardi et al. [8]
61
26–45
20.4
89 % (2 years)
66.5 % (2 years)
Baschnegel et al. [9]
47
48–60
27.6
85 % (3 years)
63 % (3 years)
Singh et al. [11]
34
40–60
16.7
88 % (2 years)
44 % (2 years)
Our series
53
50–60
13.3
86.7 (2 years)
60.4 (2 years)
centrally located lesions, and with a mortality risk \1 % [19]. It is common to observe subclinical radiological pneumonitis (G1) in imaging tests after treatment. Toxicity in this cohort was detected in 6.8 % (G2) of the cases. This low toxicity is associated with the strict compliance with limiting doses to healthy organs [13] and reduction of the prescribed dose (8 9 7.5 Gy) to centrally located tumors, to minimize the risk of bronchial stenosis/bleeding. The international registry of lung metastases treated by surgical excision published survival rates at 2, 5, and 10 years of 70, 36, and 26 %, respectively [2]. The OS at 2 years reported in larger series treated with SBRT ranges from 84 % reported by Norihisa [6] to 39 % in a multiinstitutional study [4]. OS at 1 and 2 years in our cohort was 86.7 and 60.4 % respectively. These values are within the range reported in the literature. In oligometastatic disease, it is very difficult to compare survival results between different series. The inclusion of multiple histologies, of patients with varied metastatic tumor burden, and with highly diverse prognoses (due to the underlying oncological disease) is common, in addition to different doses and techniques. Patients included in these series are also noncomparable to those which include surgical patients, because they are inoperable. Survival in our series may be associated with the inclusion of the first patients recruited at the institution. Included patients, even after multiple treatments, presented a long period between the primary diagnosis and start of SBRT (median of 22.6 months). This may indirectly lead to selecting patients with a strong tendency to be oligometastatic, as reflected by the results in terms of survival. The primary route of progression of these patients was distant progression, accounting for 25 % in our series. The current definition of an oligometastatic patient is based exclusively on clinical parameters. We need more precise biological parameters to identify this group of patients, since it is the subgroup in which reinforcing LC should improve survival. Preliminary surveys have identified a miRNA family [20] that will probably allow us to have a genomic test in the near future that objectively identifies
patients with a high probability of remaining oligometastatic over long time periods. In conclusion this study shows that SBRT is effective and safe for the treatment of lung metastases. The main failure pattern is distant progression. Randomized trials are required to quantify the impact of SBRT embedded early in systemic treatment on survival. The main, urgent goal is to identify patients with a high probability of maintaining oligometastatic status over long periods to concentrate all clinical efforts and resources on them. Conflict of interest
None.
Ethical standard The design and methodology of this study has been approved by the Ethics Committee of the Reina Sofia University Hospital of Cordoba. Informed consent
Informed consent was required.
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