- Email: [email protected]
Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients
original articles
Annals of Oncology Annals of Oncology 25: 1954–1959, 2014 doi:10.1093/annonc/mdu370 Published online 11 August 2014
Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients C. Collen1*, N. Christian1, D. Schallier2, M. Meysman3, M. Duchateau1, G. Storme1 & M. De Ridder1 Departments of 1Radiation Oncology; 2Medical Oncology; 3Respiratory Medicine, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
Background: Stereotactic body radiotherapy (SBRT) has emerged as a treatment modality in patients presenting with oligometastatic nonsmall-cell lung cancer (NSCLC). SBRT is used as a local consolidative treatment to metastatic disease sites. The majority of patients included in SBRT trials for oligometastatic NSCLC have controlled primary tumors and brain metastases. Patients and methods: Oligometastatic NSCLC patients with ≤5 metastatic lesions were included in a prospective phase II trial to evaluate efficacy and toxicity of SBRT to all disease sites, primary tumor and metastatic locations. SBRT to a dose of 50 Gy in 10 fractions was delivered. Positron emission tomography–computed tomography (PET-CT) was carried out at baseline and 3 months after SBRT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST). The progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan–Meier method from start of chemotherapy or radiotherapy. Side-effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Results: Twenty-six patients received SBRT after induction chemotherapy (n = 17) or as a primary treatment (n = 9). Median follow-up was 16.4 months. Overall metabolic response rate was 60% with seven patients (30%) achieving a complete metabolic remission and 7 (30%) a partial metabolic response. Any acute grade 2 toxicity was observed in four patients (15%) and grade 3 pulmonary toxicity in two patients (8%). Median PFS and OS were 11.2 and 23 months. The 1-year PFS and 1-year OS rate were 45% and 67%, respectively. Conclusion: SBRT to all disease sites, primary tumor and metastatic locations, in oligometastatic NSCLC patients produced an acceptable median PFS of 11.2 months. Key words: stereotactic body radiotherapy, oligometastatic NSCLC, consolidation, uncontrolled primary tumors
introduction NSCLC remains a major cause of death from cancer. Among newly diagnosed patients, 30%–50% of patients are diagnosed with metastatic disease. Moreover, in the proportion of patients initially treated with curative intent for locoregional disease, up to 40% of patients will eventually develop metastatic progression [1]. For these patients, chemotherapy is the standard of care, improving survival by 9% at 12 months in comparison with best supportive care [2]. Nevertheless, survival for stage IV NSCLC patients remains poor, with a median survival of 8 months and a 2-year survival of 10% [3].
*Correspondence to: Dr Christine Collen, Department of Radiation Oncology, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, B-1090 Brussels, Belgium. Tel: +32-2-47634-38; E-mail: [email protected]
Patients presenting with oligometastatic disease present a distinct population. There is growing evidence of the improved prognosis of a subset of this population, as demonstrated by recent reviews [4, 5]. Treatment of metastatic locations with surgery or stereotactic body radiotherapy (SBRT) has been proven feasible. For selected cases, and depending on location, the use of SBRT offers durable local control (LC) with limited toxicity [5–8]. In patients with synchronous oligometastatic NSCLC, radical treatment of the primary tumor consists of surgery, chemoradiotherapy or trimodality treatment [9, 10]. Less data are available on the efficacy and toxicity of SBRT to both the primary tumor and the metastatic locations. To be able to offer SBRT as a treatment modality to a broader population of oligometastatic NSCLC patients, a prospective study investigating the safety and efficacy of SBRT, to the primary tumor and metastatic locations, was initiated. In the present
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
Received 29 April 2014; revised 30 June 2014; accepted 27 July 2014
original articles
Annals of Oncology
article, we report on the complete metabolic response (CMR) rate, patient outcomes and toxicity.
materials and methods patient population
treatment details SBRT was delivered after induction chemotherapy or as a primary treatment in patients who were considered not to be candidates for systemic treatment because of medically unfit condition and/or low tumor burden or patients’ refusal. After SBRT, no additional treatment was offered to the patient until disease progression. In patients who received induction chemotherapy, imaging was carried out after three cycles. When a good tumor regression was observed and/or patients began to experience side-effects of chemotherapy, SBRT was initiated. The regimens consisted of a platinum-containing doublet, i.e. cisplatin or carboplatin in association with pemetrexed or gemcitabine and vinorelbine in case of nonsquamous or squamous cell carcinoma, respectively. All patients underwent a pretreatment [18F]2-fluoro-2-deoxy-D-glucose– positron emission tomography (PET) 18FDG–PET and computed tomography (CT) scan using a dedicated PET-CT camera (Gemini TF, Philips Medical Systems, OH). Radiotherapy (RT) was carried out using the TomoTherapy Hi·Art II System® (Accuray, Sunnyvale, CA) or the VERO SBRT system® (Mitsubishi Heavy Industries, Tokyo, Japan), depending on the number and distribution of the treatment sites. Both systems allow image-guided radiotherapy (IGRT) and pretreatment imaging was carried out on a daily basis. The gross tumor volume (GTV) was defined as the visible gross tumor mass on CT. Four-dimensional CT (4D CT) was not applied. No margin was added for microscopic disease extension. Treatment margins were not individualized. Instead, the planning target volume (PTV) was created by expanding the GTV by 8 mm isotropically, except for lung, adrenal and liver locations for which an increased margin of 10, 10 and 12 mm in the anteroposterior, laterolateral and craniocaudal direction, respectively, was applied. Treatment planning was carried out on the TomoTherapy TPS or iPlan 4.5-1 (Brainlab AG, Feldkirchen, Germany). The prescribed dose was 50 Gy delivered in 10 fractions of 5 Gy over 2 weeks. The planning goals have been reported in previous publications [12, 13].
toxicity scoring and treatment response evaluation Patients were invited for follow-up visits at 1 month after SBRT, every 3 months during the first 2 years and 6-monthly thereafter. No additional treatments were given in the 3 months following SBRT administration in order to allow an assessment of the acute SBRT-related toxicity according to the NCI CTCAE version 3.0. PET-CT imaging was carried out on a 3-monthly basis during the first year to assess response and disease control. Thereafter, PET-CT and appropriate CT scans were alternately carried out. Additional imaging, such as magnetic resonance imaging was
Volume 25 | No. 10 | October 2014
statistical analysis Sample size was estimated using a Richard Simon two-stage optimal design. Aiming at an overall acceptable and unacceptable CMR probability of 30% and 10%, respectively, with an α and β value of 0.10, the sample size for first and second stage 2/12 and 6/35. LC was defined as freedom from local failure in the irradiated sites and was evaluated for each irradiated site separately. Progression-free survival (PFS) was defined as freedom from local and distant recurrence. The PFS and overall survival (OS) rates were estimated by Kaplan–Meier analysis and were calculated from start of chemotherapy or RT (Figure 1). Log-rank tests were used for intergroup comparison. Statistical analyses were carried out using Statview software (SAS Institute, Inc., Cary, NC).
results patient population and treatment details Twenty-six oligometastatic NSCLC patients were included. Patients and tumors characteristics are detailed in Table 1. The population was predominantly male. Adenocarcinoma was the most frequent histology (65%). The majority of patients presented with synchronous metastasis (73%). All relevant driver mutations were evaluated. Only two patients presented with an EGFR mutation and were initially treated with a targeted agent. Initial stages were as follows: stage I (n = 2), stage IIIA (n = 4), stage IIIB (n = 3) and stage IV (n = 17), according to the American Joint Committee on Cancer (AJCC) 6th edition. Initial nodal stage was N3 in nine patients (35%). Stage IV was based on the presence of brain metastases in 5 patients (6 lesions). Patients underwent a variety of systemic and/or local therapies, such as cranial stereotactic radiosurgery (n = 5), surgery (n = 8) and chemoradiotherapy (n = 7), chemotherapy or targeted agents (n = 7) and palliative RT (n = 3), before inclusion in the trial. Treatment details are reported in Table 1. Nine patients received SBRT as a primary treatment and 17 patients after induction chemotherapy. The reasons for omitting induction chemotherapy were a combination of previous chemoradiotherapy for initial disease, advanced age, low performance status, low tumor burden and patients’ refusal. Eleven patients (42%) received three cycles of induction chemotherapy and six patients (23%) received four six cycles. Response to induction chemotherapy (n = 17) was as follows: progressive disease (n = 2), stable disease (n = 1) and partial remission (n = 14). Median interval between end of induction chemotherapy and start of hypofractionated SBRT was 41 days (range, 14–55 days). In 19 patients (73%), SBRT was delivered to the primary lung carcinoma. A total of 87 sites were irradiated of which 48 were metastatic locations. Twenty patients underwent RT on the TomoTherapy system and six patients on the VERO SBRT system.
®
®
doi:10.1093/annonc/mdu370 |
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
Eligible for this study were oligometastatic NSCLC patients with ≤5 metabolically active metastatic locations. Patients with uncontrolled primary tumors and bilateral adrenal gland metastases were eligible. Involvement of multiple mediastinal nodal stations, according to the International Association for the Study of Lung Cancer nodal atlas [11], was allowed. Each invaded lymph node station was counted as an independent irradiation site, irrespective of the number of invaded nodes. No limitations were imposed concerning the localization or dimension of the metastases. No upper age limit was defined. Patients gave written informed consent and the protocol was reviewed and approved by the institutional ethics committee.
routinely used to assess intracranial response in patients treated for brain metastases but only carried out in case of neurological symptoms in the other patients. The primary objective, CMR rate, was evaluated by comparing the 18 FDG–PET-CT at baseline with the 18FDG–PET-CT carried out 3 months after initiation of SBRT, according to PERCIST version 1.0 as previously reported [12–14].
original articles Progression-free survival
A
Annals of Oncology
1 0.8 0.6 0.4 0.2 0 0
5
10
15
20
25
30
B
1
Overall survival
0.8 0.6 0.4 0.2 0 0
5
10
15
20
25
30
35
40
45
Time (in months) Figure 1. (A) Kaplan–Meier plot of progression-free survival (PFS) rate for all patients. (B) Kaplan–Meier plot of overall survival (OS) for all patients.
toxicity and treatment response The 3-month treatment-free interval was respected in 24 patients. In one patient, symptomatic brain metastases were diagnosed and whole-brain RT was initiated. Acute grade 2 toxicity occurred in four patients (15%). Toxicities observed were: dyspnea (n = 1) and dysphagia (n = 2) and pneumonitis (n = 1). Two patients (8%) experienced a grade 3 acute toxicity, namely cough with resolution of symptoms after 6 weeks and pneumonitis requiring hospital admission, oxygen therapy and steroids. Two of four patients that presented with grade 2 or 3 pulmonary toxicity were retreated with SBRT after initial chemoradiotherapy for primary tumor. No major late toxicity was observed in any of the patients. Metabolic response could be evaluated in 23 patients or in 72 of 87 sites irradiated. In three patients, no 18FDG–PET-CT scan could be carried out because of PD (n = 1), early death (n = 1) and patients refusal (n = 1). Metabolic response rates were as follows: 7 patients (30%) achieved a CMR and 7 patients (30%) a PMR, resulting in an overall metabolic response rate of 60%. At 3 months, three patients presented with distant disease progression only and one patient with combined local and distant failure. Median follow-up of was 16.4 months (range, 3–40 months). At the time of analysis, seven patients (27%) did not develop
| Collen et al.
disease recurrence. The ultimate recurrence pattern was local only in 3 patients (16%), distant only in 6 (32%) and combined in 10 (52%). The median PFS was 11.2 months with a 1-year PFS rate of 45%. Failure in irradiated sites was observed in 11 of 72 evaluable sites (15%). Location of in-field failures was as follows: in primary disease sites (n = 3), adrenal gland metastases (n = 3), lung metastasis (n = 3), bone metastasis (n = 1) and liver metastasis (n = 1). In our dataset, log-rank comparison between groups with and without induction chemotherapy revealed no statistically significant difference for LC (P = 0.5034) or DFS (P = 0.1342). The median OS was 23 months and the 1-year OS rate was 67%, with 14 patients still alive at time of analysis. In univariate analysis, PET response positively correlated with improved PFS (P = 0.0308, log rank) but not with OS (P = 0.118, log rank). The OS was significantly better in case of synchronous metastases and induction chemotherapy (P = 0.0145 and P = 0.0446, respectively). No impact of sex, histology was noted on PFS or OS (data not shown). Salvage treatment after SBRT was started in all 19 patients that experienced disease progression and consisted of systemic therapy (n = 9), whole-brain RT (n = 3) and a variety of local treatment options such as a second course of SBRT for distant
Volume 25 | No. 10 | October 2014
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
Time (in months)
original articles
Annals of Oncology
Table 1. Patient, tumor characteristics and treatment details (N = 26) 62 (47–75) 20 (77%)/6 (23%) 9 (35%) 14 (54%) 3 (11%) 17 (65%) 2 (8%) 3 (12%) 4 (15%) 19 (73%) 7 (27%) 9 (35%) 11 (42%) 6 (23%) 5 (26%) 7 (37%) 2 (11%) 3 (15%) 2 (11%) 5 (26%) 4 (22%) 3 (15%) 7 (37%) 1 (0–4) 1 (1–5) 14 (54%) 12 (46%) 2 (1–5) 14 (54%) 8 (31%) 4 (15%) 1 (2%) 9 (19%) 15 (31%) 8 (16%) 6 (13%) 3 (6%) 6 (13%) 7.2 (0.2–65)
WHO, World Health Organization; NOS, not otherwise specified; T, tumor stage; N, nodal stage; PLNS, positive lymph node stations; GTV, gross tumor volume.
failure (n = 2), surgery for skin metastasis (n = 1) or relapsed adrenal gland metastasis (n = 2) and RFA of the lung (n = 1). After local salvage treatment, five patients (83%) remained
Volume 25 | No. 10 | October 2014
discussion Local consolidative treatment of metastatic locations with surgical metastasectomy and SBRT has recently emerged as an additional treatment modality of oligometastatic patients, as pointed out in a review by Ashworth et al. [4]. The majority of patients recruited are relatively young (median age of 60 years), have a good performance status, a controlled primary tumor (82%), a low number of metastatic sites (1–3, 50% solitary) and suffer from brain metastases only (60%). In this selected population, a median OS of 14.8 months (range, 5.9–52 months) was observed. Highly significant prognostic factors on multivariate analysis were: definitive treatment of the primary tumor, N stage and disease-free interval of at least 6–12 months [4]. In most studies of local consolidative treatment of oligometastatic disease, stringent inclusion criteria apply in terms of number, volume and location of the metastases [8]. A milder form of hypofractionation was therefore chosen for the present study, allowing a broader applicability. As suggested by Tree et al. [8], viable tumor cells can be eradicated by doses lower than the ablative schedules in the former trials. A dose of 50 Gy delivered in 5 Gy fractions, assuming the α/β ratio to be 10, results in a biological equivalent dose of 75 Gy which is able to achieve LC and delay progression and is supported by clinical data from trials on SBRT for extracranial oligometastases in different sites [12, 13, 15, 16]. Milano et al. [15] reported a 2-year LC rate of 74% with this schedule in a nonbreast cancer population. We therefore applied the previously established 10-fraction schedule but applied it to all sites of disease, primary tumor and metastatic locations. Regarding the type of local treatment that we offered to our patients, it is questioned if the primary tumor site should also be treated by SBRT. We observed three failures after SBRT to the primary tumor site (tumor and nodes) on 34 primary sites irradiated (9%), compared with 5% in the series of De Ruysscher et al. [9]. In the latter study, 39 synchronous oligometastatic NSCLC patients received standard chemoradiotherapy to the primary tumor in combination with different types of radical local treatment to metastatic locations. The median PFS and OS was 12.1 and 13.5 months, respectively, calculated from date of diagnosis. Despite the fact that we observed more metabolic reactivation in primary disease sites in our population, our median PFS of 11.2 months and median OS of 23 months compare favorably with the results by De Ruysscher et al., indicating that SBRT to the primary tumor is an acceptable treatment modality. Griffioen et al. [10] reported results of a multi-institutional trial in 63 synchronous oligometastatic NSCLC patients receiving definitive treatment to primary tumor by chemoradiotherapy, surgery and stereotactic RT, depending on
doi:10.1093/annonc/mdu370 |
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
Age (years): mean, (range) Male/female, n (%) WHO performance status 0 1 2 Pathology Adenocarcinoma Squamous cell carcinoma Other NSCLC NOS Occurrence of metastases Synchronous Metachronous Number of induction chemotherapy cycles 0 3 4–6 Treatment of local disease (N = 19) T1 T2 T3 T4 Recurrent primary N0 N1 N2 N3 PLNS median (range) Number of metastatic lesions treated Median (range) 1 metastatic lesion, n (%) >1 metastatic lesion, n (%) Number of involved organs per patient Median (range) 1 2–3 4–5 Localization of metastases (N = 48) Thyroid Metastatic lymph node stations Lung/pleura Bone/muscle Adrenal gland Liver Brain Volume of metastases (ml) Mean GTV volume (range)
disease free without further therapy. Whole-brain RT resulted in a median time to intracranial disease progression of 9.8 months (range, 3.0–17.9 months). The median duration on salvage systemic treatment was 4.0 months (1.2–15.3 months) and resulted in disease stabilization in three patients (33%). Median survival after first progression was 4.9 months (range, 1.4–28.6 months) with an observed median survival of 10.4 months (range, 7.0– 28.6 months) after salvage local treatment and 6.6 months (range, 1.4–12.5 months) for patients under systemic treatment.
original articles
| Collen et al.
SBRT has the advantage of a short overall treatment time and the favorable toxicity profile makes it a good treatment alternative to maintenance chemotherapy. A large randomized phase II study, SABR-COMET, is ongoing evaluating the impact of SBRT to metastatic locations on quality of life (QOL) and OS, compared with standard of care treatment alone [19]. In the absence of randomized, controlled trial data supporting the use of local consolidative treatment, SBRT cannot be offered outside of a clinical trial context. The results of our prospective phase II study add to the growing body of evidence on efficacy of local treatment of metastatic locations but also provide data on efficacy of SBRT to primary tumors in patients with synchronous oligometastatic NSCLC. Our future research we will emphasize more on the effect of SBRT on QoL, an aspect not prospectively evaluated in the current trial.
conclusion This prospective phase II study with SBRT in oligometastatic NSCLC patients shows the feasibility of the approach in a population of patients presenting with uncontrolled primary tumors, bulky nodal disease, predominantly extracranial and multiple metastatic locations. Toxicity was acceptable but caution is advised in case of re-irradiation of primary tumors. From this small study, we cannot conclude that SBRT to the primary tumor should become a treatment option for synchronous oligometastatic NSCLC patients but it is a therapeutic option that results in acceptable PFS. Randomized trials with evaluation of QoL, PFS and OS should be conducted between definitive treatment to the primary tumor and local treatment to metastatic locations and SBRT to all disease sites.
disclosure The authors have declared no conflicts of interest.
references 1. Aupérin A, Le Péchoux C, Rolland E et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 2181–2190. 2. Non-Small Cell Lung Cancer collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2010; 5: CD007309. 3. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 4. Ashworth A, Rodrigues G, Boldt G et al. Is there an oligometastatic state in nonsmall cell lung cancer? A systematic review of the literature. Lung Cancer 2013; 82: 197–203. 5. Salah S, Tanvetyanon T, Abbasi S. Metastatectomy for extra-cranial extra-adrenal non-small cell lung cancer solitary metastases: systematic review and analysis of reported cases. Lung Cancer 2012; 75: 9–14. 6. Yano T, Haro A, Yoshida T. Prognostic impact of local treatment against postoperative oligometastases in NSCLC. J Surg Oncol 2010; 102: 852–855. 7. Alongi F, Arcangeli S, Filippi A et al. Review and uses of stereotactic body radiation therapy for oligometastases. Oncologist 2012; 17: 1100–1107. 8. Tree A, Khoo V, Eeles R et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol 2013; 14: 28–637. 9. De Ruysscher D, Wanders R, van Baardwijk A et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases:
Volume 25 | No. 10 | October 2014
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
tumor stage, in combination with RT and surgery modalities to the metastatic locations. They reported a 2-year survival rate of 38% in a patient population with 82% solitary metastases. Our 2-year OS rate is 49% in a population with only 54% solitary metastases. The only study that previously investigated the use of SBRT to the primary tumor was the trial by Hasselle et al. [16]. Fifteen patients (60%) of 25 included, received SBRT to the primary tumor. Different dose schedules were used, a 10-fraction regimen to 50 Gy and a 3-fraction regimen to a dose of 24–36 Gy. At 12 months, OS was 81% and PFS 42%, in comparison with 67% and 45%, respectively, in the present study. Comparison between both trials is however difficult because of the different dose regimens used, the heterogeneous patient populations and the relative small sample sizes in both trials. The use of SBRT as a treatment modality to the primary tumor is currently investigated in an ongoing trial (NCT 01185639). Most other trials, evaluating the efficacy of SBRT in oligometastatic NSCLC patients, used standard definitive treatment approaches to the primary tumor. Our observed acute toxicity rate of 8% is comparable with reports by other groups [9, 16], but caution is advised in case of re-irradiation of primary tumors. Local recurrence rate in our study was 15%. It is hypothesized that a geographical miss could be the reason for ∼50% of these local recurrences. In fact, no real motion management was implemented in this trial, except for an increased craniocaudal PTV margin expansion in case of moving lesions located in the lung, adrenal gland or liver. LC rate can be improved if RT delivery is explored to its full technical extent by implementing 4D CT and respiratory motion management. In contrast to the findings of other authors [17], in our population, the observed OS was significantly better in the patients with synchronous metastases and after induction chemotherapy. More deaths occurred in the group with metachronous metastases besides the relative long disease-free interval. The median disease-free interval was 19.9 months (range, 3.6–48.7 months), with only two patients failing within the first 12 months. Possible explanations could be that 78% of patients were treated with primary SBRT without any systemic therapy for metastatic progression, all metastases were extracranial and only 33% were solitary lesions. We concluded for our future practice that in case of metachronous metastatic disease progression, systemic treatment should be re-initiated unless patients are unfit. Furthermore, we could not observe a prognostic effect of sex or histology, but our population included only four females with adenocarcinoma histology which makes definitive conclusions inappropriate. When looking at the characteristics of this patient sample, we offered SBRT to a patient population often treated with palliative chemotherapy. The majority of patients had synchronous metastases, uncontrolled primary tumors and predominantly extracranial metastatic localizations. Compared with other therapeutic alternatives a median PFS of 11.2 months is encouraging. Pemetrexed administered as maintenance therapy, offered a PFS of 4.1 months with a median OS of 13.9 months in the Paramount study [18]. This seems lower than in the present study; however, a difference in tumor burden cannot be excluded.
Annals of Oncology
original articles
Annals of Oncology
10.
11.
12. 13.
14.
15. Milano MT, Katz AW, Zhang H et al. Oligometastases treated with stereotactic body radiotherapy: long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys 2012; 83: 878–886. 16. Hasselle M, Haraf D, Rusthoven K et al. Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer. J Thorac Oncol 2012; 7: 379–381. 17. De Vin T, Engels B, Gevaert T et al. Stereotactic radiotherapy for oligometastatic cancer: a prognostic model for survival. Ann Oncol 2014; 25: 467–471. 18. Paz-Ares LG, de Marinis F, Dediu M et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013; 31: 2895–2902. 19. Palma DA, Haasbeek C, Rodrigues G et al. Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): study protocol for a randomized phase II trial. BMC Cancer 2012; 12: 305.
Annals of Oncology 25: 1959–1965, 2014 doi:10.1093/annonc/mdu288 Published online 25 July 2014
Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer F. Rothé1, J.-F. Laes5, D. Lambrechts6,7, D. Smeets6,7, D. Vincent1, M. Maetens1, D. Fumagalli1, S. Michiels8, S. Drisis2, C. Moerman2, J.-P. Detiffe5, D. Larsimont3, A. Awada4, M. Piccart4, C. Sotiriou1,4,† & M. Ignatiadis1,4,†* 1 Breast Cancer Translational Research Laboratory J.C. Heuson; Departments of 2Radiology; 3Pathology; 4Medical Oncology, Université Libre de Bruxelles, Institut Jules Bordet, Brussels; 5OncoDNA, Gosselies; 6Laboratory of Translational Genetics, KU Leuven, Leuven; 7Vesalius Research Center, VIB, Leuven, Belgium; 8Department of Biostatistic and Epidemiology, Gustave Roussy, Univ. Paris-Sud, Villejuif, France
Received 4 July 2014; revised 16 July 2014; accepted 20 July 2014
Background: Molecular screening programs use next-generation sequencing (NGS) of cancer gene panels to analyze metastatic biopsies. We interrogated whether plasma could be used as an alternative to metastatic biopsies. Patients and methods: The Ion AmpliSeq™ Cancer Hotspot Panel v2 (Ion Torrent), covering 2800 COSMIC mutations from 50 cancer genes was used to analyze 69 tumor (primary/metastases) and 31 plasma samples from 17 metastatic breast cancer patients. The targeted coverage for tumor DNA was ×1000 and for plasma cell-free DNA ×25 000. Whole blood normal DNA was used to exclude germline variants. The Illumina technology was used to confirm observed mutations. Results: Evaluable NGS results were obtained for 60 tumor and 31 plasma samples from 17 patients. When tumor samples were analyzed, 12 of 17 (71%, 95% confidence interval (CI) 44% to 90%) patients had ≥1 mutation (median 1 mutation per patient, range 0–2 mutations) in either p53, PIK3CA, PTEN, AKT1 or IDH2 gene. When plasma samples were analyzed, 12 of 17 (71%, 95% CI: 44–90%) patients had ≥1 mutation (median 1 mutation per patient, range 0–2 mutations) in either p53, PIK3CA, PTEN, AKT1, IDH2 and SMAD4. All mutations were confirmed. When we focused on tumor and plasma samples collected at the same time-point, we observed that, in four patients, no mutation was
*Correspondence to: Dr Michaill Ignatiadis, Department of Medical Oncology and Breast Cancer Translational Research Laboratory, J.C. Heuson, Université Libre de Bruxelles, Institut Jules Bordet, Rue Héger-Bordet 1, 1000 Brussels, Belgium. Tel: +32-2-541-72-81; E-mail: [email protected] †
CS and MI are last co-authors.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
long-term results of a prospective phase II trial. J Thorac Oncol 2012; 7: 1547–1555. Griffioen G, Toguri D, Dahele M et al. Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): patient outcomes and prognostic factors. Lung Cancer 2013; 82: 95–102. Rusch V, Asamura H, Watanabe H et al. on behalf of the members of the IASLC Staging Committee. The IASLC Lung Cancer Staging Project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009; 4: 568–577. Engels B, Everaert H, Gevaert T et al. Phase II study of helical tomotherapy for oligometastatic colorectal cancer. Ann Oncol 2011; 22: 362–368. Engels B, Gevaert T, Everaert H et al. Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer. Radiat Oncol 2012; 7: 34. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009; 50: 122S–150S.
Annals of Oncology Annals of Oncology 25: 1954–1959, 2014 doi:10.1093/annonc/mdu370 Published online 11 August 2014
Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients C. Collen1*, N. Christian1, D. Schallier2, M. Meysman3, M. Duchateau1, G. Storme1 & M. De Ridder1 Departments of 1Radiation Oncology; 2Medical Oncology; 3Respiratory Medicine, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
Background: Stereotactic body radiotherapy (SBRT) has emerged as a treatment modality in patients presenting with oligometastatic nonsmall-cell lung cancer (NSCLC). SBRT is used as a local consolidative treatment to metastatic disease sites. The majority of patients included in SBRT trials for oligometastatic NSCLC have controlled primary tumors and brain metastases. Patients and methods: Oligometastatic NSCLC patients with ≤5 metastatic lesions were included in a prospective phase II trial to evaluate efficacy and toxicity of SBRT to all disease sites, primary tumor and metastatic locations. SBRT to a dose of 50 Gy in 10 fractions was delivered. Positron emission tomography–computed tomography (PET-CT) was carried out at baseline and 3 months after SBRT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST). The progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan–Meier method from start of chemotherapy or radiotherapy. Side-effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Results: Twenty-six patients received SBRT after induction chemotherapy (n = 17) or as a primary treatment (n = 9). Median follow-up was 16.4 months. Overall metabolic response rate was 60% with seven patients (30%) achieving a complete metabolic remission and 7 (30%) a partial metabolic response. Any acute grade 2 toxicity was observed in four patients (15%) and grade 3 pulmonary toxicity in two patients (8%). Median PFS and OS were 11.2 and 23 months. The 1-year PFS and 1-year OS rate were 45% and 67%, respectively. Conclusion: SBRT to all disease sites, primary tumor and metastatic locations, in oligometastatic NSCLC patients produced an acceptable median PFS of 11.2 months. Key words: stereotactic body radiotherapy, oligometastatic NSCLC, consolidation, uncontrolled primary tumors
introduction NSCLC remains a major cause of death from cancer. Among newly diagnosed patients, 30%–50% of patients are diagnosed with metastatic disease. Moreover, in the proportion of patients initially treated with curative intent for locoregional disease, up to 40% of patients will eventually develop metastatic progression [1]. For these patients, chemotherapy is the standard of care, improving survival by 9% at 12 months in comparison with best supportive care [2]. Nevertheless, survival for stage IV NSCLC patients remains poor, with a median survival of 8 months and a 2-year survival of 10% [3].
*Correspondence to: Dr Christine Collen, Department of Radiation Oncology, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, B-1090 Brussels, Belgium. Tel: +32-2-47634-38; E-mail: [email protected]
Patients presenting with oligometastatic disease present a distinct population. There is growing evidence of the improved prognosis of a subset of this population, as demonstrated by recent reviews [4, 5]. Treatment of metastatic locations with surgery or stereotactic body radiotherapy (SBRT) has been proven feasible. For selected cases, and depending on location, the use of SBRT offers durable local control (LC) with limited toxicity [5–8]. In patients with synchronous oligometastatic NSCLC, radical treatment of the primary tumor consists of surgery, chemoradiotherapy or trimodality treatment [9, 10]. Less data are available on the efficacy and toxicity of SBRT to both the primary tumor and the metastatic locations. To be able to offer SBRT as a treatment modality to a broader population of oligometastatic NSCLC patients, a prospective study investigating the safety and efficacy of SBRT, to the primary tumor and metastatic locations, was initiated. In the present
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
Received 29 April 2014; revised 30 June 2014; accepted 27 July 2014
original articles
Annals of Oncology
article, we report on the complete metabolic response (CMR) rate, patient outcomes and toxicity.
materials and methods patient population
treatment details SBRT was delivered after induction chemotherapy or as a primary treatment in patients who were considered not to be candidates for systemic treatment because of medically unfit condition and/or low tumor burden or patients’ refusal. After SBRT, no additional treatment was offered to the patient until disease progression. In patients who received induction chemotherapy, imaging was carried out after three cycles. When a good tumor regression was observed and/or patients began to experience side-effects of chemotherapy, SBRT was initiated. The regimens consisted of a platinum-containing doublet, i.e. cisplatin or carboplatin in association with pemetrexed or gemcitabine and vinorelbine in case of nonsquamous or squamous cell carcinoma, respectively. All patients underwent a pretreatment [18F]2-fluoro-2-deoxy-D-glucose– positron emission tomography (PET) 18FDG–PET and computed tomography (CT) scan using a dedicated PET-CT camera (Gemini TF, Philips Medical Systems, OH). Radiotherapy (RT) was carried out using the TomoTherapy Hi·Art II System® (Accuray, Sunnyvale, CA) or the VERO SBRT system® (Mitsubishi Heavy Industries, Tokyo, Japan), depending on the number and distribution of the treatment sites. Both systems allow image-guided radiotherapy (IGRT) and pretreatment imaging was carried out on a daily basis. The gross tumor volume (GTV) was defined as the visible gross tumor mass on CT. Four-dimensional CT (4D CT) was not applied. No margin was added for microscopic disease extension. Treatment margins were not individualized. Instead, the planning target volume (PTV) was created by expanding the GTV by 8 mm isotropically, except for lung, adrenal and liver locations for which an increased margin of 10, 10 and 12 mm in the anteroposterior, laterolateral and craniocaudal direction, respectively, was applied. Treatment planning was carried out on the TomoTherapy TPS or iPlan 4.5-1 (Brainlab AG, Feldkirchen, Germany). The prescribed dose was 50 Gy delivered in 10 fractions of 5 Gy over 2 weeks. The planning goals have been reported in previous publications [12, 13].
toxicity scoring and treatment response evaluation Patients were invited for follow-up visits at 1 month after SBRT, every 3 months during the first 2 years and 6-monthly thereafter. No additional treatments were given in the 3 months following SBRT administration in order to allow an assessment of the acute SBRT-related toxicity according to the NCI CTCAE version 3.0. PET-CT imaging was carried out on a 3-monthly basis during the first year to assess response and disease control. Thereafter, PET-CT and appropriate CT scans were alternately carried out. Additional imaging, such as magnetic resonance imaging was
Volume 25 | No. 10 | October 2014
statistical analysis Sample size was estimated using a Richard Simon two-stage optimal design. Aiming at an overall acceptable and unacceptable CMR probability of 30% and 10%, respectively, with an α and β value of 0.10, the sample size for first and second stage 2/12 and 6/35. LC was defined as freedom from local failure in the irradiated sites and was evaluated for each irradiated site separately. Progression-free survival (PFS) was defined as freedom from local and distant recurrence. The PFS and overall survival (OS) rates were estimated by Kaplan–Meier analysis and were calculated from start of chemotherapy or RT (Figure 1). Log-rank tests were used for intergroup comparison. Statistical analyses were carried out using Statview software (SAS Institute, Inc., Cary, NC).
results patient population and treatment details Twenty-six oligometastatic NSCLC patients were included. Patients and tumors characteristics are detailed in Table 1. The population was predominantly male. Adenocarcinoma was the most frequent histology (65%). The majority of patients presented with synchronous metastasis (73%). All relevant driver mutations were evaluated. Only two patients presented with an EGFR mutation and were initially treated with a targeted agent. Initial stages were as follows: stage I (n = 2), stage IIIA (n = 4), stage IIIB (n = 3) and stage IV (n = 17), according to the American Joint Committee on Cancer (AJCC) 6th edition. Initial nodal stage was N3 in nine patients (35%). Stage IV was based on the presence of brain metastases in 5 patients (6 lesions). Patients underwent a variety of systemic and/or local therapies, such as cranial stereotactic radiosurgery (n = 5), surgery (n = 8) and chemoradiotherapy (n = 7), chemotherapy or targeted agents (n = 7) and palliative RT (n = 3), before inclusion in the trial. Treatment details are reported in Table 1. Nine patients received SBRT as a primary treatment and 17 patients after induction chemotherapy. The reasons for omitting induction chemotherapy were a combination of previous chemoradiotherapy for initial disease, advanced age, low performance status, low tumor burden and patients’ refusal. Eleven patients (42%) received three cycles of induction chemotherapy and six patients (23%) received four six cycles. Response to induction chemotherapy (n = 17) was as follows: progressive disease (n = 2), stable disease (n = 1) and partial remission (n = 14). Median interval between end of induction chemotherapy and start of hypofractionated SBRT was 41 days (range, 14–55 days). In 19 patients (73%), SBRT was delivered to the primary lung carcinoma. A total of 87 sites were irradiated of which 48 were metastatic locations. Twenty patients underwent RT on the TomoTherapy system and six patients on the VERO SBRT system.
®
®
doi:10.1093/annonc/mdu370 |
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
Eligible for this study were oligometastatic NSCLC patients with ≤5 metabolically active metastatic locations. Patients with uncontrolled primary tumors and bilateral adrenal gland metastases were eligible. Involvement of multiple mediastinal nodal stations, according to the International Association for the Study of Lung Cancer nodal atlas [11], was allowed. Each invaded lymph node station was counted as an independent irradiation site, irrespective of the number of invaded nodes. No limitations were imposed concerning the localization or dimension of the metastases. No upper age limit was defined. Patients gave written informed consent and the protocol was reviewed and approved by the institutional ethics committee.
routinely used to assess intracranial response in patients treated for brain metastases but only carried out in case of neurological symptoms in the other patients. The primary objective, CMR rate, was evaluated by comparing the 18 FDG–PET-CT at baseline with the 18FDG–PET-CT carried out 3 months after initiation of SBRT, according to PERCIST version 1.0 as previously reported [12–14].
original articles Progression-free survival
A
Annals of Oncology
1 0.8 0.6 0.4 0.2 0 0
5
10
15
20
25
30
B
1
Overall survival
0.8 0.6 0.4 0.2 0 0
5
10
15
20
25
30
35
40
45
Time (in months) Figure 1. (A) Kaplan–Meier plot of progression-free survival (PFS) rate for all patients. (B) Kaplan–Meier plot of overall survival (OS) for all patients.
toxicity and treatment response The 3-month treatment-free interval was respected in 24 patients. In one patient, symptomatic brain metastases were diagnosed and whole-brain RT was initiated. Acute grade 2 toxicity occurred in four patients (15%). Toxicities observed were: dyspnea (n = 1) and dysphagia (n = 2) and pneumonitis (n = 1). Two patients (8%) experienced a grade 3 acute toxicity, namely cough with resolution of symptoms after 6 weeks and pneumonitis requiring hospital admission, oxygen therapy and steroids. Two of four patients that presented with grade 2 or 3 pulmonary toxicity were retreated with SBRT after initial chemoradiotherapy for primary tumor. No major late toxicity was observed in any of the patients. Metabolic response could be evaluated in 23 patients or in 72 of 87 sites irradiated. In three patients, no 18FDG–PET-CT scan could be carried out because of PD (n = 1), early death (n = 1) and patients refusal (n = 1). Metabolic response rates were as follows: 7 patients (30%) achieved a CMR and 7 patients (30%) a PMR, resulting in an overall metabolic response rate of 60%. At 3 months, three patients presented with distant disease progression only and one patient with combined local and distant failure. Median follow-up of was 16.4 months (range, 3–40 months). At the time of analysis, seven patients (27%) did not develop
| Collen et al.
disease recurrence. The ultimate recurrence pattern was local only in 3 patients (16%), distant only in 6 (32%) and combined in 10 (52%). The median PFS was 11.2 months with a 1-year PFS rate of 45%. Failure in irradiated sites was observed in 11 of 72 evaluable sites (15%). Location of in-field failures was as follows: in primary disease sites (n = 3), adrenal gland metastases (n = 3), lung metastasis (n = 3), bone metastasis (n = 1) and liver metastasis (n = 1). In our dataset, log-rank comparison between groups with and without induction chemotherapy revealed no statistically significant difference for LC (P = 0.5034) or DFS (P = 0.1342). The median OS was 23 months and the 1-year OS rate was 67%, with 14 patients still alive at time of analysis. In univariate analysis, PET response positively correlated with improved PFS (P = 0.0308, log rank) but not with OS (P = 0.118, log rank). The OS was significantly better in case of synchronous metastases and induction chemotherapy (P = 0.0145 and P = 0.0446, respectively). No impact of sex, histology was noted on PFS or OS (data not shown). Salvage treatment after SBRT was started in all 19 patients that experienced disease progression and consisted of systemic therapy (n = 9), whole-brain RT (n = 3) and a variety of local treatment options such as a second course of SBRT for distant
Volume 25 | No. 10 | October 2014
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
Time (in months)
original articles
Annals of Oncology
Table 1. Patient, tumor characteristics and treatment details (N = 26) 62 (47–75) 20 (77%)/6 (23%) 9 (35%) 14 (54%) 3 (11%) 17 (65%) 2 (8%) 3 (12%) 4 (15%) 19 (73%) 7 (27%) 9 (35%) 11 (42%) 6 (23%) 5 (26%) 7 (37%) 2 (11%) 3 (15%) 2 (11%) 5 (26%) 4 (22%) 3 (15%) 7 (37%) 1 (0–4) 1 (1–5) 14 (54%) 12 (46%) 2 (1–5) 14 (54%) 8 (31%) 4 (15%) 1 (2%) 9 (19%) 15 (31%) 8 (16%) 6 (13%) 3 (6%) 6 (13%) 7.2 (0.2–65)
WHO, World Health Organization; NOS, not otherwise specified; T, tumor stage; N, nodal stage; PLNS, positive lymph node stations; GTV, gross tumor volume.
failure (n = 2), surgery for skin metastasis (n = 1) or relapsed adrenal gland metastasis (n = 2) and RFA of the lung (n = 1). After local salvage treatment, five patients (83%) remained
Volume 25 | No. 10 | October 2014
discussion Local consolidative treatment of metastatic locations with surgical metastasectomy and SBRT has recently emerged as an additional treatment modality of oligometastatic patients, as pointed out in a review by Ashworth et al. [4]. The majority of patients recruited are relatively young (median age of 60 years), have a good performance status, a controlled primary tumor (82%), a low number of metastatic sites (1–3, 50% solitary) and suffer from brain metastases only (60%). In this selected population, a median OS of 14.8 months (range, 5.9–52 months) was observed. Highly significant prognostic factors on multivariate analysis were: definitive treatment of the primary tumor, N stage and disease-free interval of at least 6–12 months [4]. In most studies of local consolidative treatment of oligometastatic disease, stringent inclusion criteria apply in terms of number, volume and location of the metastases [8]. A milder form of hypofractionation was therefore chosen for the present study, allowing a broader applicability. As suggested by Tree et al. [8], viable tumor cells can be eradicated by doses lower than the ablative schedules in the former trials. A dose of 50 Gy delivered in 5 Gy fractions, assuming the α/β ratio to be 10, results in a biological equivalent dose of 75 Gy which is able to achieve LC and delay progression and is supported by clinical data from trials on SBRT for extracranial oligometastases in different sites [12, 13, 15, 16]. Milano et al. [15] reported a 2-year LC rate of 74% with this schedule in a nonbreast cancer population. We therefore applied the previously established 10-fraction schedule but applied it to all sites of disease, primary tumor and metastatic locations. Regarding the type of local treatment that we offered to our patients, it is questioned if the primary tumor site should also be treated by SBRT. We observed three failures after SBRT to the primary tumor site (tumor and nodes) on 34 primary sites irradiated (9%), compared with 5% in the series of De Ruysscher et al. [9]. In the latter study, 39 synchronous oligometastatic NSCLC patients received standard chemoradiotherapy to the primary tumor in combination with different types of radical local treatment to metastatic locations. The median PFS and OS was 12.1 and 13.5 months, respectively, calculated from date of diagnosis. Despite the fact that we observed more metabolic reactivation in primary disease sites in our population, our median PFS of 11.2 months and median OS of 23 months compare favorably with the results by De Ruysscher et al., indicating that SBRT to the primary tumor is an acceptable treatment modality. Griffioen et al. [10] reported results of a multi-institutional trial in 63 synchronous oligometastatic NSCLC patients receiving definitive treatment to primary tumor by chemoradiotherapy, surgery and stereotactic RT, depending on
doi:10.1093/annonc/mdu370 |
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
Age (years): mean, (range) Male/female, n (%) WHO performance status 0 1 2 Pathology Adenocarcinoma Squamous cell carcinoma Other NSCLC NOS Occurrence of metastases Synchronous Metachronous Number of induction chemotherapy cycles 0 3 4–6 Treatment of local disease (N = 19) T1 T2 T3 T4 Recurrent primary N0 N1 N2 N3 PLNS median (range) Number of metastatic lesions treated Median (range) 1 metastatic lesion, n (%) >1 metastatic lesion, n (%) Number of involved organs per patient Median (range) 1 2–3 4–5 Localization of metastases (N = 48) Thyroid Metastatic lymph node stations Lung/pleura Bone/muscle Adrenal gland Liver Brain Volume of metastases (ml) Mean GTV volume (range)
disease free without further therapy. Whole-brain RT resulted in a median time to intracranial disease progression of 9.8 months (range, 3.0–17.9 months). The median duration on salvage systemic treatment was 4.0 months (1.2–15.3 months) and resulted in disease stabilization in three patients (33%). Median survival after first progression was 4.9 months (range, 1.4–28.6 months) with an observed median survival of 10.4 months (range, 7.0– 28.6 months) after salvage local treatment and 6.6 months (range, 1.4–12.5 months) for patients under systemic treatment.
original articles
| Collen et al.
SBRT has the advantage of a short overall treatment time and the favorable toxicity profile makes it a good treatment alternative to maintenance chemotherapy. A large randomized phase II study, SABR-COMET, is ongoing evaluating the impact of SBRT to metastatic locations on quality of life (QOL) and OS, compared with standard of care treatment alone [19]. In the absence of randomized, controlled trial data supporting the use of local consolidative treatment, SBRT cannot be offered outside of a clinical trial context. The results of our prospective phase II study add to the growing body of evidence on efficacy of local treatment of metastatic locations but also provide data on efficacy of SBRT to primary tumors in patients with synchronous oligometastatic NSCLC. Our future research we will emphasize more on the effect of SBRT on QoL, an aspect not prospectively evaluated in the current trial.
conclusion This prospective phase II study with SBRT in oligometastatic NSCLC patients shows the feasibility of the approach in a population of patients presenting with uncontrolled primary tumors, bulky nodal disease, predominantly extracranial and multiple metastatic locations. Toxicity was acceptable but caution is advised in case of re-irradiation of primary tumors. From this small study, we cannot conclude that SBRT to the primary tumor should become a treatment option for synchronous oligometastatic NSCLC patients but it is a therapeutic option that results in acceptable PFS. Randomized trials with evaluation of QoL, PFS and OS should be conducted between definitive treatment to the primary tumor and local treatment to metastatic locations and SBRT to all disease sites.
disclosure The authors have declared no conflicts of interest.
references 1. Aupérin A, Le Péchoux C, Rolland E et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 2181–2190. 2. Non-Small Cell Lung Cancer collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2010; 5: CD007309. 3. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 4. Ashworth A, Rodrigues G, Boldt G et al. Is there an oligometastatic state in nonsmall cell lung cancer? A systematic review of the literature. Lung Cancer 2013; 82: 197–203. 5. Salah S, Tanvetyanon T, Abbasi S. Metastatectomy for extra-cranial extra-adrenal non-small cell lung cancer solitary metastases: systematic review and analysis of reported cases. Lung Cancer 2012; 75: 9–14. 6. Yano T, Haro A, Yoshida T. Prognostic impact of local treatment against postoperative oligometastases in NSCLC. J Surg Oncol 2010; 102: 852–855. 7. Alongi F, Arcangeli S, Filippi A et al. Review and uses of stereotactic body radiation therapy for oligometastases. Oncologist 2012; 17: 1100–1107. 8. Tree A, Khoo V, Eeles R et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol 2013; 14: 28–637. 9. De Ruysscher D, Wanders R, van Baardwijk A et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases:
Volume 25 | No. 10 | October 2014
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
tumor stage, in combination with RT and surgery modalities to the metastatic locations. They reported a 2-year survival rate of 38% in a patient population with 82% solitary metastases. Our 2-year OS rate is 49% in a population with only 54% solitary metastases. The only study that previously investigated the use of SBRT to the primary tumor was the trial by Hasselle et al. [16]. Fifteen patients (60%) of 25 included, received SBRT to the primary tumor. Different dose schedules were used, a 10-fraction regimen to 50 Gy and a 3-fraction regimen to a dose of 24–36 Gy. At 12 months, OS was 81% and PFS 42%, in comparison with 67% and 45%, respectively, in the present study. Comparison between both trials is however difficult because of the different dose regimens used, the heterogeneous patient populations and the relative small sample sizes in both trials. The use of SBRT as a treatment modality to the primary tumor is currently investigated in an ongoing trial (NCT 01185639). Most other trials, evaluating the efficacy of SBRT in oligometastatic NSCLC patients, used standard definitive treatment approaches to the primary tumor. Our observed acute toxicity rate of 8% is comparable with reports by other groups [9, 16], but caution is advised in case of re-irradiation of primary tumors. Local recurrence rate in our study was 15%. It is hypothesized that a geographical miss could be the reason for ∼50% of these local recurrences. In fact, no real motion management was implemented in this trial, except for an increased craniocaudal PTV margin expansion in case of moving lesions located in the lung, adrenal gland or liver. LC rate can be improved if RT delivery is explored to its full technical extent by implementing 4D CT and respiratory motion management. In contrast to the findings of other authors [17], in our population, the observed OS was significantly better in the patients with synchronous metastases and after induction chemotherapy. More deaths occurred in the group with metachronous metastases besides the relative long disease-free interval. The median disease-free interval was 19.9 months (range, 3.6–48.7 months), with only two patients failing within the first 12 months. Possible explanations could be that 78% of patients were treated with primary SBRT without any systemic therapy for metastatic progression, all metastases were extracranial and only 33% were solitary lesions. We concluded for our future practice that in case of metachronous metastatic disease progression, systemic treatment should be re-initiated unless patients are unfit. Furthermore, we could not observe a prognostic effect of sex or histology, but our population included only four females with adenocarcinoma histology which makes definitive conclusions inappropriate. When looking at the characteristics of this patient sample, we offered SBRT to a patient population often treated with palliative chemotherapy. The majority of patients had synchronous metastases, uncontrolled primary tumors and predominantly extracranial metastatic localizations. Compared with other therapeutic alternatives a median PFS of 11.2 months is encouraging. Pemetrexed administered as maintenance therapy, offered a PFS of 4.1 months with a median OS of 13.9 months in the Paramount study [18]. This seems lower than in the present study; however, a difference in tumor burden cannot be excluded.
Annals of Oncology
original articles
Annals of Oncology
10.
11.
12. 13.
14.
15. Milano MT, Katz AW, Zhang H et al. Oligometastases treated with stereotactic body radiotherapy: long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys 2012; 83: 878–886. 16. Hasselle M, Haraf D, Rusthoven K et al. Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer. J Thorac Oncol 2012; 7: 379–381. 17. De Vin T, Engels B, Gevaert T et al. Stereotactic radiotherapy for oligometastatic cancer: a prognostic model for survival. Ann Oncol 2014; 25: 467–471. 18. Paz-Ares LG, de Marinis F, Dediu M et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013; 31: 2895–2902. 19. Palma DA, Haasbeek C, Rodrigues G et al. Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): study protocol for a randomized phase II trial. BMC Cancer 2012; 12: 305.
Annals of Oncology 25: 1959–1965, 2014 doi:10.1093/annonc/mdu288 Published online 25 July 2014
Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer F. Rothé1, J.-F. Laes5, D. Lambrechts6,7, D. Smeets6,7, D. Vincent1, M. Maetens1, D. Fumagalli1, S. Michiels8, S. Drisis2, C. Moerman2, J.-P. Detiffe5, D. Larsimont3, A. Awada4, M. Piccart4, C. Sotiriou1,4,† & M. Ignatiadis1,4,†* 1 Breast Cancer Translational Research Laboratory J.C. Heuson; Departments of 2Radiology; 3Pathology; 4Medical Oncology, Université Libre de Bruxelles, Institut Jules Bordet, Brussels; 5OncoDNA, Gosselies; 6Laboratory of Translational Genetics, KU Leuven, Leuven; 7Vesalius Research Center, VIB, Leuven, Belgium; 8Department of Biostatistic and Epidemiology, Gustave Roussy, Univ. Paris-Sud, Villejuif, France
Received 4 July 2014; revised 16 July 2014; accepted 20 July 2014
Background: Molecular screening programs use next-generation sequencing (NGS) of cancer gene panels to analyze metastatic biopsies. We interrogated whether plasma could be used as an alternative to metastatic biopsies. Patients and methods: The Ion AmpliSeq™ Cancer Hotspot Panel v2 (Ion Torrent), covering 2800 COSMIC mutations from 50 cancer genes was used to analyze 69 tumor (primary/metastases) and 31 plasma samples from 17 metastatic breast cancer patients. The targeted coverage for tumor DNA was ×1000 and for plasma cell-free DNA ×25 000. Whole blood normal DNA was used to exclude germline variants. The Illumina technology was used to confirm observed mutations. Results: Evaluable NGS results were obtained for 60 tumor and 31 plasma samples from 17 patients. When tumor samples were analyzed, 12 of 17 (71%, 95% confidence interval (CI) 44% to 90%) patients had ≥1 mutation (median 1 mutation per patient, range 0–2 mutations) in either p53, PIK3CA, PTEN, AKT1 or IDH2 gene. When plasma samples were analyzed, 12 of 17 (71%, 95% CI: 44–90%) patients had ≥1 mutation (median 1 mutation per patient, range 0–2 mutations) in either p53, PIK3CA, PTEN, AKT1, IDH2 and SMAD4. All mutations were confirmed. When we focused on tumor and plasma samples collected at the same time-point, we observed that, in four patients, no mutation was
*Correspondence to: Dr Michaill Ignatiadis, Department of Medical Oncology and Breast Cancer Translational Research Laboratory, J.C. Heuson, Université Libre de Bruxelles, Institut Jules Bordet, Rue Héger-Bordet 1, 1000 Brussels, Belgium. Tel: +32-2-541-72-81; E-mail: [email protected] †
CS and MI are last co-authors.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on August 21, 2015
long-term results of a prospective phase II trial. J Thorac Oncol 2012; 7: 1547–1555. Griffioen G, Toguri D, Dahele M et al. Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): patient outcomes and prognostic factors. Lung Cancer 2013; 82: 95–102. Rusch V, Asamura H, Watanabe H et al. on behalf of the members of the IASLC Staging Committee. The IASLC Lung Cancer Staging Project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009; 4: 568–577. Engels B, Everaert H, Gevaert T et al. Phase II study of helical tomotherapy for oligometastatic colorectal cancer. Ann Oncol 2011; 22: 362–368. Engels B, Gevaert T, Everaert H et al. Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer. Radiat Oncol 2012; 7: 34. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009; 50: 122S–150S.