European Journal of Cancer (2015) xxx, xxx– xxx

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Stereotactic body radiation therapy for lung metastases from soft tissue sarcoma Pierina Navarria a, Anna Maria Ascolese a, Luca Cozzi a,⇑, Stefano Tomatis a, Giuseppe Roberto D’Agostino a, Fiorenza De Rose a, Rita De Sanctis b, Andrea Marrari b, Armando Santoro b, Antonella Fogliata a, Umberto Cariboni c, Marco Alloisio c, Vittorio Quagliuolo d, Marta Scorsetti a a

Radiosurgery and Radiotherapy Department, Istituto Clinico Humanitas Cancer Center and Research Hospital, Rozzano, Milan, Italy Oncology and Haematology Department, Istituto Clinico Humanitas Cancer Center and Research Hospital, Rozzano, Milan, Italy c Thoracic Surgery Department, Istituto Clinico Humanitas Cancer Center and Research Hospital, Rozzano, Milan, Italy d General Surgery Department, Istituto Clinico Humanitas Cancer Center and Research Hospital, Rozzano, Milan, Italy b

Received 11 December 2014; received in revised form 17 January 2015; accepted 22 January 2015

KEYWORDS Soft tissue sarcoma Lung RapidArc Stereotactic body radiation therapy

Abstract Purpose: To appraise the role of stereotactic body radiation therapy (SBRT) in patients with lung metastasis from primary soft tissue sarcoma. Methods: Twenty-eight patients (51 lesions) were analysed. All patients were in good performance status (1–2 eastern cooperative oncology group (ECOG)), unsuitable for surgical resection, with controlled primary tumour and the number of lung metastases was 64. In a risk adaptive scheme, the dose prescription was: 30 Gy/1 fr, 60 Gy/3 fr, 60 Gy/8 fr and 48 Gy/4 fr. Treatments were performed with Volumetric Modulated Arc Therapy. Clinical outcome was evaluated by thoracic and abdominal computed tomography (CT) scan before SBRT and than every 3 months. Toxicity was evaluated with Common Terminology Criteria for Adverse Events (CTCAE) scale version 4.0. Results: Leiomyosarcoma (36%) and synovial sarcoma (25%) were the most common histologies. Five patients (18%) initially presented with pulmonary metastasis, whereas 23 (82%) developed them at a median time of 51 months (range 11–311 months) from the initial diagnosis. The median follow-up time from initial diagnosis was 65 months (5–139 months) and from SBRT was 21 months (2–80 months). No severe toxicity (grades III–IV) was recorded and no patients required hospitalisation. The actuarial 5-years local control rate (from SBRT treatment) was 96%. Overall survival at 2 and 5 years was 96.2% and 60.5%, respectively. At last follow-up 15 patients (54%) were alive. All other died because of distant progression.

⇑ Corresponding author at: Humanitas Research Hospital, Istituto Clinico Humanitas, Via Manzoni 56, 20089, Rozzano, Milan, Italy. Tel.: +41 79 7166321; fax: +39 02248509. E-mail address: [email protected] (L. Cozzi).

http://dx.doi.org/10.1016/j.ejca.2015.01.061 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.

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P. Navarria et al. / European Journal of Cancer xxx (2015) xxx–xxx

Conclusions: SBRT provides excellent local control of pulmonary metastasis from soft tissue sarcoma (STS) and may improve survival in selected patients. SBRT should be considered for all patients with pulmonary metastasis (PM) and evaluated in a multidisciplinary team. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Soft tissue sarcomas (STSs) are malignancies of mesenchymal origin which represent about 1% of adult’s tumours [1]. Despite adequate treatment, 25–50% of patients with localised disease develop distant metastases [2–4], most frequently in the lungs. Metastatic status at the time of first diagnosis is not uncommon [5]. Depending on the number of the metastases, the site and the disease free interval (DFI) surgery or chemotherapy may be offered [6] Patients with indolent diseases may benefit from repeated surgical resections [7]. Conversely, patients with bilateral, rapidly progressing lung metastases are usually managed with chemotherapy or investigational therapies. Radiation therapy to the lung has been traditionally reserved to patients unfit for surgery. However, with the recent technological improvements, the indications for radiation therapy are broadening [3]. Stereotactic body radiation therapy (SBRT), which allows for accurate delivery of high dose radiation to the target, proved to be effective in the treatment of metastatic lesions to the lungs and liver [8]. Few reports of SBRT in lung metastases from STS are available [9–11], showing excellent local control with minimal toxicity. In the effort to determine the role of SBRT in the treatment of patients with lung sarcoma metastases, we retrospectively review the medical records of the patients treated at our institution. 2. Methods and material 2.1. Patients and procedures The present prospective observational study, approved by local ethical committee, includes patients with lung metastases from soft tissue sarcoma (STS). At the initial diagnosis of primary tumour, all patients undergone open-surgery resection, followed by radiotherapy and/or adjuvant chemotherapy. At the time of recurrence, they were evaluated for salvage treatment, which included surgical resection, stereotactic body radiation therapy (SBRT) and chemotherapy. After receiving study approval from the institutional review board, to define the appropriate patient therapeutic strategy, each patient was evaluated by a multidisciplinary board including a medical oncologist, a radiation oncologist and a thoracic surgeon. The patients’ general condition (age, performance status, symptoms) and

disease status (other site of metastases, number of lung metastases, time to progression) were considered. SBRT was performed in case of one or more of the following: (1) indolent behaviour disease, (2) controlled primary tumour, (3) metastatic lesion less than five such as the definition of oligometastatic patients (4) pulmonary ipsilateral or bilateral disease, (5) progressive disease after chemotherapy and/or surgical resection, (6) contraindication to surgical resection, (7) synchronous lung lesions up to four. From February 2008 to May 2014, 28 consecutive patients referred at our institution for metastatic lung soft tissue sarcoma, for a total of 51 lung lesions eventually underwent SBRT and were included in the study. Of these patients, 16 (57%) were female and 12 (43%) male with a median age of 64 years (range 23–89 years). The most common primary tumour was leiomyosarcoma 10 (36%) and the most common primary site of disease was the extremities 13 (46%). Lung metastatic lesions were present at diagnosis in five (18%) patients, whereas they developed in 23 (82%) patients after primary tumour treatment. At the time of SBRT, 23 (82%) patients had only lung lesions and five (18%) had additional metastatic localisations, one patient had a stable residual retroperitoneal tumour and four one isolated bone metastases. SBRT was performed as first treatment of lung metastases in six patients (no pathological confirmation was available for these patients), while in 22 patients it was performed at progression of lung lesions after chemotherapy and/or surgical resection of other metastases in the lungs. In 16 patients with single lung metastases, SBRT rather than surgery was performed for the following reasons: previous multiple surgical resection (8 pts), and/or advanced age and comorbidity (3 pts), and/or short Disease Free Interval (DFI) from diagnosis to appearance of lung metastases (3 pts), and/or site of occurrence (four patients with central lesions) and patient refusal (2 pts). Patient’s characteristics and treatment are shown in Table 1. 2.2. SBRT treatment A 4D-CT scan was acquired for all patients before SBRT. The Clinical Target Volume (CTV, coincident in the study to the gross tumour volume GTV) was delineated on each 4D-CT phase to generate Internal Target Volume (ITV); the ITV was defined as the

Please cite this article in press as: Navarria P. et al., Stereotactic body radiation therapy for lung metastases from soft tissue sarcoma, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.01.061

P. Navarria et al. / European Journal of Cancer xxx (2015) xxx–xxx Table 1 Patient characteristics and treatments of lung metastases. No.

%

Gender Female Male

16 12

Median age

64 years

Histology of primary tumour Leiomyosarcoma Synovial sarcoma Spindle cell Sarcoma Other

10 4 3 11

36 14 5 45

Site of primary tumour Extremities Trunk Head and neck Pelvis Uterus Retroperitoneum

13 7 1 2 3 2

46 25 4 7 11 7

Stage at diagnosis Localised disease Metastatic disease

23 5

82 18

Treatment at diagnosis of lung metastases Chemotherapy 5 Surgery 10 Surgery and chemotherapy 7 SBRT 6 Number of lung metastases treated with SBRT Total doses and schedule of SBRT 30 Gy in 1 fractions 60 Gy in 3 fractions 48 Gy in 4 fractions 60 Gy in 8 fractions

53 43 (range 23–89 years)

18 36 25 21

51

100

2 7 38 4

4 14 74 8

SBRT, stereotactic body radiation therapy.

envelope of the CTVs from each respiratory phase. The Planning Target Volume (PTV) was defined as an isotropic 3 mm expansion from the ITV. Organs at risks (OARs) considered were: lungs, heart, spinal cord, oesophagus and chest wall. The dose prescription was modulated according to a risk adaptive protocol (based on the site and the size of the lesions): 30 Gy/1 fr for peripheral lesions 610 mm, 60 Gy/3 fr for peripheral lesions between 10 and 20 mm, 48 Gy/4 fr for peripheral lesions >20 mm and 60 Gy/8 fr for central lesions. Central lesions were defined as tumours located in the proximal bronchial tree zone as defined by the Radiation Therapy Oncology Group (a, b) and/or located 61 cm from the heart or mediastinum. The proximal bronchial tree includes the carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus, and right and left lower lobe bronchi; the proximal bronchial tree zone extends 2 cm in all directions [12,13]. All these fractionation schemes guaranteed a BED >100 Gy, assuming an ab = 10 for tumours. Plans were normalised to the mean dose to the CTV.

3

The plan objective was to cover at least 98% of the CTV (ITV) volume with 98% of the prescribed dose (V98% = 98%) and for the PTV to cover 95% of the volume with 95% of the dose (V95% = 95%). All treatments were optimised and delivered for Volumetric Modulated Arc Therapy in the RapidArc form on a TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, United States of America (USA)); six or 10MV conventional or Flattening filter free (FFF) photon beams were used to enhance delivery efficiency. Daily patient set-up was realised by multi-image guided radiation therapy (IGRT) approach using 3D cone beam CT (CBCT) images. Free breathing delivery was chosen for all patients. 2.3. Outcome evaluation Clinical outcome was evaluated by clinical examination and thoracic and abdominal CT scan before and after treatment and then every 3 months thereafter. Response was defined as the reduction greater than 30% of maximum diameter, disappearance of the lesions at CT scan, or stability of lesion at CT scan with negative 18FDG PET-CT. Any growing lesion not clearly ascribable to fibrosis was reported as Progression of Disease (PD). Toxicity was recorded using Common Terminology Criteria for Adverse Events version 4.0. 2.4. Statistical analysis Standard descriptive statistics (mean standard deviation and cross tabulation analysis) was used to describe the data general behaviour. Local control (LC) and overall survival (OS) were computed by means of Kaplan–Meier analysis, starting from the date of diagnosis, recurrence and SBRT treatment. Univariate analysis was performed with the log-rank test to investigate the prognostic role of individual variables. 3. Results The median time from diagnosis to the appearance of lung metastases was 18 months (range 0–168 months). Before SBRT, 10 (36%) patients underwent surgical resection for other lung metastases, five (18%) patients received chemotherapy, and seven (25%) patients received both treatments; SBRT was performed as first treatment in six (21%) patients and in 28 patients at disease progression after previous therapy. No salvage surgery was performed after SBRT; at distant progression 10 patients received further chemotherapy. A total of 51 SBRT were performed in 28 patients at a median time of 16 months (range 0–107 months) from lung progression (discovery of metastases) and at a median time from previous treatment of 14 months (range 0–107). The treated lesions were seven in one patients, three in

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six patients, two in five patients and one in 16 patients. Thirty-eight solitary lung metastases were treated in 16 patients while in five and one patients, two and three synchronous metastases respectively were treated. The multiple lesions were located in the same lung for five patients and bilateral in 1. The median total size of the lung metastases was 6.5 cm3 (range 0.5–100 cm3). The mean PTV volume was 44.5 ± 42.1 cm3 (range: 3.2–187.2 cm3). The total dose prescribed was 60 Gy for four central lung lesions and seven peripheral lung lesions between 10 and 20 mm, 48 Gy for 38 lung lesions greater than 20 mm and 30 Gy in single fraction for two peripheral lung lesion smaller than 10 mm. The median follow up time from diagnosis was 55 months (range 17–251 months) and from the development of lung metastasis was 39 months (range 0–119 months). In evaluable patients no progression in the same site of treatment was recorded. The crude local control was 96%. One young patient, with RMSA in head and neck region, died because of early ubiquitaire progression before the radiological response assessment. Fig. 1 shows an example of complete remission of lung metastases on CT scan performed at 6 months after SBRT. The mean LC time from SBRT treatment was 77.6 ± 2.1 months (95% confidence interval (C.I.):74– 82 months); the median was not reached. The 2- and 5-years local control from SBRT was 96.2 ± 3.0%. Fig. 2 shows the actuarial LC graph. The median overall survival (OS) from diagnoses was 78.7 ± 71.6 months (95%C.I.: 0–219 months). The 2-years actuarial OS was 96.2 ± 3.8% and the 5-years OS was 60.5 ± 9.8%. The median OS from evidence of lung metastases was 70.0 ± 24.6 months (range 22– 118 months; 95%C.I.: 22–118). The 2-years actuarial OS was 84.9 ± 7.0% and the 5-years OS was 53.6 ± 10.4%. The median OS from SBRT was 27.8 ± 9.6 months (range 8–47 months; 95%C.I.: 8–47) and the 2- and 5-years OS was 55.7 ± 10.9% and 43.3 ± 11.5%. Fig. 3a and b shows the OS from diagnosis and from SBRT treatment. With a median

Fig. 2. Actuarial local control from stereotactic body radiation therapy (SBRT) treatment.

observation time of 55 months (range 17–251 months), 15 (54%) patients are alive and 13 (46%) died. On univariate analysis, survival was not related to age, gender, histology and site of primary tumour, presence of other metastatic site, or doses of SBRT prescribed. In our cohort, only the disease free interval (DFI) from diagnosis, significantly affected survival; patients with DFI greater than 24 months had the longest survival; the 3 and 5 years OS was 88% compared with 67% and 33% (p = 0.02). Fig. 3c shows the OS stratified for the three groups of patient. No severe pulmonary toxicity (grades III–IV) occurred in our series and the clinical evaluation score during follow up remained stable. Grade I–II toxicity was recorded in 18 (64%) patients and it was visible on CT scan at 9 and 12 months; no correlation with PTV size or number of lesions was observed. No increase of corticosteroid drug was needed in any patients.

60 Gy in 3 fractions

Before SBRT

At 3 months after SBRT

At 6 months after SBRT

Fig. 1. Response after 3 and 6 months from stereotactic body radiation therapy (SBRT) of a lung metastasis.

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P. Navarria et al. / European Journal of Cancer xxx (2015) xxx–xxx

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Fig. 3. (a) Actuarial overall survival from diagnosis; (b) Actuarial overall survival from stereotactic body radiation therapy (SBRT) treatment; (c) Actuarial overall survival from diagnosis stratified for the time-to-metastasis free interval.

4. Discussion Metastatic STS patients have poor prognosis with 3-year survival rate of 20–30%. Therefore, in order to reach a systemic control with no further spread of disease, they are theoretically candidate to chemotherapy. Doxorubicin-based regimens remain the ‘gold standard’ in the treatment of advanced STS with an overall response rate of about 20%. Anthracycline analogues such as alternative drugs (trabectedin, gemcitabine, taxanes, dacarbazine, pazopanib, sorafenib) are currently employed but none of them have a superior efficacy than

doxorubicin [14–17]. In a recent report by the French sarcoma group emerges a potential efficacy of local ablative treatment on the survival of patients with oligometastases (one to five lesions, any metastatic site, any grade/histology) from sarcomas [18] On the other hand, the lungs are the most common sites of metastatic disease. Approximately 20% of metastatic STS patient have isolated pulmonary metastases. Histological grade, performance of metastasis resection and disease-free interval remain the main prognostic factors [19]. In well-selected cases of pulmonary metastasis (PM) from STS amenable to resection, the 3-year OS after

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Table 2 Published studies about stereotactic body radiation therapy (SBRT) in lung metastatic patients from soft tissue sarcomas (STS). No. of pts No. of Time from lesions diagnosis to PM Dhakal et al. [9] 14 Soyfer et al. [11] 22

74 53

Mehta et al. [10] 16

25

SBRT total dose/fr LC

0.7 years (0.3–7.3 years) 50 Gy/5 nv 40 Gy/4 60 Gy/3 nv 54 Gy/3–4

OS

Toxicity

83% Median 2.1 years (range 0.8–11.5 years) No PGrade 3 100% 50% at 5 years 1 Grade 3 94% 72% at 4 years

No Grade 2–4

LC, local control; OS, overall survival; SBRT, stereotactic body radiation therapy.

surgery has been reported and ranged from 23% to 71% in different series, with a relatively significant proportion of long-term survivors (7–18%) [20]. In some series, the median OS was 45 months after complete resection [21]. Billingsley and colleagues reported the results of 719 patients with lung metastases of whom 161 underwent complete surgical resection: these patients had a median survival of 33 months and a 3-year actuarial survival rate of 46% [22]. However, the majority of published data describe mixed series of patients with bone or soft-tissue sarcoma with different 1-year OS, between 39–50% and 18–44% respectively [23–27]. It would seem that surgical pulmonary resection is the only treatment option. Although surgical management of PM from STS undoubtedly remains the primary treatment modality, in more recent years also SBRT has been investigated. To date, only few reports have been published and all of them are retrospective studies. In another study, 15 patients underwent SBRT. No severe toxicity was recorded and the 3 years LC was 82% with a median OS of 2.1 years (range 0.8– 11.5 years) [8]. Soyfer et al. evaluated 22 patients for 53 lung lesions treated by SBRT [11]. No progressive disease of all SBRT treated lesions was found at a median follow-up of 95 months (SD 32). Five-year overall survival was 62% from the time of diagnosis and 50% from start of treatment with minimal toxicity. Mehta et al. reported the results of mixed series treated with SBRT. 16 patients for 25 lung lesions were evaluated. The local control rate at 43 months was 94% [10]. Table 2 shows patients and treatments details about published studies. In our series only patients with lung metastases exclusively from STS (no bone sarcoma) were included. Fifty-one lesions in 28 patients were treated with SBRT. By use of this approach, long-lasting remission of treated lung metastases was obtained in all patients. These results compare favourably with previous reports [9–11]. Survival rates were also highly satisfactory, with an overall survival from diagnosis of 80% and 61% at 3 and 5 years respectively and from SBRT of 86% and 43% at 1 and 2 years respectively. In relation to the few published data on SBRT in lung metastatic STS, no data about prognostic factors are available, if not resulting from surgical series. In oligometastatic patients undergoing SBRT for lung lesions from different solid tumours, factors associated to better survival are long DFI, number of metastatic lesions, controlled primary

tumour and histology. In our series all patients had controlled primary tumour and few metastatic sites between one and four. The only factors significantly affecting survival were the DFI from diagnoses to development of lung metastases (p = 0.02). According to total doses prescribed and fractionation used no differences were recorded. These data are probably due to the fact that in all cases the BED was greater than 100. Finally no severe, grade III–IV pulmonary toxicity was registered such as already reported in literature. 5. Conclusion The study demonstrated that, in patients with lung metastases from STS, SBRT is feasible with limited toxicity. The clinical results obtained are highly satisfactory. From our experience, we believe that the discussion of each single case within a multidisciplinary team (oncologist, radiation oncologist, thoracic surgeon) is of pivotal importance to drive the most appropriate therapeutic approach. Well-designed collaborative trials are necessary to draw final conclusions in this field. Conflict of interest statement L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Clinical Research Scientist at Humanitas Cancer Center. All other co-authors have no conflicts of interests. No other conflicts nor funding sources should be disclosed. References [1] Fletcher CD et al., Pathology and genetics of tumours of soft tissue and bone, WHO classification of tumours; 2014. [2] Gronchi A, Colombo C, Raut CP. Surgical management of localized soft tissue tumours. Cancer 2014;120:2638–48. [3] DeLaney TF, Trofimov AV, Engelsman M, Suit HD. Advancedtechnology radiation therapy in the management of bone and soft tissue sarcomas. Cancer Control 2005;12:27–35. [4] Le Cesne A, Ouali M, Leahy MG, Santoro A, Hoekstra HJ, Hohenberger P, et al. Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials. Ann Oncol 2014;25:2425–32. [5] Ferguson PC, Deheshi BM, Chung P, Catton CN, O’Sullivan B, Gupta A, et al. Soft tissue sarcoma presenting with metastatic disease: outcome with primary surgical resection. Cancer 2011;117:372–9.

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