Total tumor volume as a predictor of survival in patients with multiple oligometastases treated with stereotactic ablative radiotherapy (SABR)

Total tumor volume as a predictor of survival in patients with multiple oligometastases treated with stereotactic ablative radiotherapy (SABR) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Total tumor volume as a predictor of survival in patients with multiple oligometastases treated with stereotactic ablative radiotherapy (SABR) Ciro Franzese, Veronica Vernier, Davide Franceschini, Tiziana Comito, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2835255/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jun, 2023 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted 7 You are reading this latest preprint version Abstract Background: Delivering stereotactic ablative radiotherapy (SABR) in patients with multiple oligometastases represents a challenge for clinical and technical reasons. We aimed to evaluate the outcome of patients affected by multiple oligometastases treated with SABR and the impact of tumor volume on survival. Materials and methods: We included all the patients treated with single course SABR for 3 to 5 extracranial oligometastases. All patients were treated with the volumetric modulated arc therapy (VMAT) technique with ablative intent. End-points of the analysis were overall survival (OS), progression free survival (PFS), local control (LC) and toxicity. Results: 136 patients were treated from 2012 to 2020 on 451 oligometastases. Most common primary tumor was colorectal cancer (44.1%) followed by lung cancer (11.8%). A total of 3, 4 and 5 lesions were simultaneously treated in 102 (75.0%), 26 (19.1%), and 8 (5.9%) patients, respectively. Median total tumor volume (TTV) was 19.1 cc (range 0.6 - 245.1). With a median follow-up of 25.0 months, OS at 1 and 3 years was 88.4% and 50.2%, respectively. Increasing TTV was independent predictive factor of worse OS (HR 2.37, 95%CI 1.18 – 4.78, p=0.014) and PFS (HR 1.63, 95%CI 1.05 – 2.54; p=0.028). Median OS was 80.6 months if tumor volume was ≤ 10 cc (1 and 3 years OS rate 93.6% and 77.5%, respectively), and 31.1 months if TTV was higher than 10 cc (1 and 3 years OS rate 86.7% and 42.3%, respectively). Rates of LC at 1 and 3 years were 89.3% and 76.5%. In terms of toxicity, no grade 3 or higher toxicity was reported both in the acute and late settings. Conclusion: We demonstrated the impact of tumor volume on survival and disease control of patients affected by multiple oligometastases treated with single course SABR. oligometastatic SBRT SABR stereotactic radiotherapy oligometastases multiple radiosurgery stereotactic ablative radiotherapy Figures Figure 1 Figure 2 Introduction The oligometastatic state was first defined in 1995 as an intermediate state between localized and widespread diffuse disease[1]. However, it is now recognized as a heterogeneous setting that includes patients who differ from each other in several characteristics, including timing of appearance of metastases and the extent of disease. Recently, the ESTRO-EORTC consensus recommendation established a classification of these patients into subcategories based on 17 disease characterization factors and 5 different questions[2]. Stereotactic ablative radiotherapy (SABR) emerged in the last years as an effective local treatment for patients with a limited number of metastases. For example, Gomez et al.[3] evaluated the impact of local consolidative therapy in addition to standard of care in patients with 3 or fewer metastases from non-small cell lung cancer (NSCLC), showing a median overall survival (OS) of 41.2 months in the local treatment arm vs 17.0 months in the standard of care arm (p=0.017). A significant benefit was also demonstrated by Iyengar et al.[4] in a prospective trial that included oligometastatic NSCLC patients with no more than 3 lesions in the liver or lung. Currently, the oligometastatic state is defined only by the maximum number of metastases visible on diagnostic imaging, typically ranging from 1 to 3 lesions[5–8], as there are no validated biomarkers to confirm the existence of limited burden of disease. Nevertheless, delivering SABR in patients with multiple metastases remains a challenge from both the clinical and technical perspectives, and only a few patients with 3 or more lesions have been included in most studies on the oligometastatic disease [9–13]. Indeed, it is matter of debate whether the limit to metastases’ ablation should be numerical or related to the technical feasibility and the risk of toxicity. In the document by Lievens et al.[14] a consensus was reached on the possibility of safely delivering curative intent metastasis-directed radiotherapy instead of limiting the maximum number of oligometastases. In the present study, we aimed to evaluate survival and toxicity of a large sample of patients affected by multiple oligometastases treated with single course SABR, and to evaluate the impact of tumor volume on patients’ outcome. Materials And Methods We included in this retrospective analysis patients treated in our Institution with a single course of SABR on 3 to 5 extracranial oligometastases from any solid tumors. Patients with brain metastases or malignant pleural effusion were excluded from the analysis. Each case was discussed with a multidisciplinary board to reach consensus on the optimal therapeutic strategy. The local ethic committee approved the analysis. The study was conducted in accordance with the Good Clinical Practice guidelines, the ethical principles of the Declaration of Helsinki and local regulations. All the patients were simulated with a CT scan, registered with MRI or PET scan when available. All patients were positioned supine and immobilized with a thermoplastic mask. The clinical target volume (CTV) was equal to the gross tumor volume (GTV) and an isotropic margin of 3 - 10 mm, depending on disease site and dimensions, was added to the CTV to obtain the planning target volume (PTV). All patients were treated with the volumetric modulated arc therapy (VMAT) technique. The patient’s position was evaluated daily with cone-beam CT imaging before each treatment session. To compare the different treatment schedule, the biological effective dose (BED) was calculated. The linear quadratic model used for calculation was [15] : BED was calculated with a α/β of 10. The Equivalent dose in 2Gy fractions (EQD2) was calculated with the following formula: Clinical and radiological evaluation with CT or MRI scan was carried out every 3 months after SABR. The tumor response was classified according to the European Organization for Research and Treatment of Cancer Response Evaluation Criteria In Solid Tumours (EORTC-RECIST) criteria version 1.16. End-points of the analysis were OS, progression free survival (PFS), local control (LC) and pattern of toxicity. The OS was calculated from SABR to death from any cause or last follow-up. The PFS was defined as the time from treatment to in-field or out-field progression or death from any cause. The LC was calculated from SBRT to first in-field progression, death from any cause or last-follow-up. Univariate analysis was carried out using the Log-rank test and Cox proportional hazards regression was used to estimate hazard ratios for the potential risk factors. Variables with a value 0.05 at univariate test were selected for the multivariable Cox regression analysis carried out to evaluate the association between clinical factors and survival. Statistical calculations were carried out using STATA, version 15. Results We included a total of 136 patients treated with SABR from 2012 to 2020 on 451 oligometastases. Patients’ and disease’s characteristics are described in Table 1. Median age was 67.8 years (range 28.0 – 87.1), and majority of patients was male (58.8%). Most common primary tumor was colorectal cancer (60, 44.1%) followed by lung cancer (16, 11.8) and prostate cancer (8, 5.9%). Median disease-free interval (DFI) calculated from diagnosis of primary tumor to first appearance of metastases was 14.1 months (range 0 – 222.1). A total of 39 (28.7%) patients had synchronous metastatic disease. According to ESTRO-EORTC consensus, majority of patients was classified as induced oligorecurrence (25, 18.38%), and repeat oligorecurrence (59, 43.38%). Fifty-four (39.7%) patients had previous local treatment before SABR, and 22 (16.2%) patients received 3 or more lines of systemic therapies before treatment. A total of 3, 4 or 5 lesions were simultaneously treated in 102 (75.0%), 26 (19.1%), and 8 (5.9%) patients. Median total tumor volume (TTV) was 19.1 cc with a range of 0.6 to 245.1 cc. Site of metastases treated with SBRT were lung, liver, lymph node, pancreas, adrenal gland, and bones, both spine and non-spine. Multiple lesions in the lung were treated in 47 (34.6%) patients, and in the liver in 31 (22.8%) cases. Two or three organs were treated simultaneously in 36 (26.5%) and 3 (2.2%) patients, respectively. In 17 (12.5%) patients was present extra-target disease as non-irradiated metastases already in control by the on-going systemic therapy. Median EQD2 was 83.3 Gy with a range from 37.5 to 218.7 Gy. An EQD2 of 70 – 100 Gy was adopted in 64 (47.1%) patients and > 100 Gy in 15 (11.0%) patients. With a median follow-up of 25.0 months, rates of OS at 1 and 3 years were 88.4% (95%CI 81.5 – 92.8) and 50.2% (95%CI 40.5 – 59.2). Results of univariate analysis are reported in Table 2. On univariate analysis, higher age, higher Eastern Cooperative Oncology Group (ECOG) performance status (PS), lower EQD2 and higher TTV were associated with worse OS. An EQD2 > 50 Gy and TTV ≤ 10 cc were associated with the lowest risk of death. At multivariable analysis, however only increasing TTV was predictive of worse OS with an HR of 2.37 (95%CI 1.18 – 4.78, p=0.014). Figure 1 illustrate Kaplan-Meier curves for OS of the whole population and according to TTV. Median OS was 80.6 months if tumor volume was ≤ 10 cc (1 and 3 years OS rate 93.6% and 77.5%, respectively), and 31.1 months if TTV was higher than 10 cc (1 and 3 years OS rate 86.7% and 42.3%, respectively). We didn’t observe a correlation neither between LC and OS (p=0.216) nor LC and PFS (p=0.549). Median PFS of the whole group was 8.06 months. Rates of PFS at 1 and 3 years were 34.8% (95%CI 26.9 – 42.9) and 6.5% (95%CI 2.9 – 12.1) as shown in Figure 2. At univariate analysis, number of treated organs, non-liver metastases, minimum EQD2 and TTV were significantly associated with PFS. At multivariable analysis, only TTV remained a negative predictive factor for PFS (HR 1.63, 95%CI 1.05 – 2.54; p=0.028). A total of 47 (38.2%) patients intensified, switched, or activated systemic therapy after SABR. At first progression after SABR, 96 (71.6%) patients had 5 or less metastatic progressions, while 38 (28.4%) patients were diagnosed with poliprogressive disease. Globally a total of 50 (36.8%) patients had polymetastatic progression during follow-up. Sixty-seven (53.2%) patients received a second course of local ablative treatment. Local progression of the treated metastases was observed in 80 (17.7%) lesions and 42 (30.9%) patients with a median LC not achieved. Rates of LC at 1 and 3 years analyzed at lesions’ level were 89.3% (95%CI 85.9 – 91.9) and 76.5% (95%CI 71.2 – 80.4). At univariate analysis, a volume larger than 50 cc was associated with lower LC (HR 2.38, 1.47 – 3.84; p=0.000) while the use of concomitant systemic therapies was a positive predictive factor (HR 0.26, 95%CI 0.12 – 0.58; p=0.001). There was a trend of significance for the dose in terms of EQD2 (HR 0.99, 95%CI 0.98 – 1.00; p=0.058). At multivariable analysis, the volume (HR 1.92, 95%CI 1.18 – 3.12; p=0.009), concomitant treatment (HR 0.28, 95%CI 0.13 – 0.62; p=0.02) and the dose (HR 0.99, 95%CI 0.98 – 0.99; p=0.049) were statistically significant for LC. We made a subgroup analysis according to TTV to evaluate the impact of dose on defined population. For patients with TTV ≤ 10 cc, the minimum EQD2 was not correlated with OS (HR 0.67, 95%CI 0.23 – 1.99; p=0.478). For patients with TTV > 10 cc, the increasing EQD2 was associated with longer survival (HR 0.98, 95%CI 0.97 – 0.99; p=0.018), with a median OS of 21.2 months for EQD2 ≤ 50 Gy and 31.9 months for EQD2 > 50. Nevertheless, the dose was not correlated with PFS in both TTV ≤ 50 cc (HR 0.99, 95%CI 0.98 – 1.00; p=0.066) and > 50 cc (HR 0.99, 95%CI 0.98 – 1.00; p=0.319). In terms of toxicity, in the acute setting we observed 26 (21.0%) patients and 11 (8.9%) patients reporting grade 1 and grade 2 side effect, respectively. Most commonly acute toxicities included fatigue (11 instances), pain (11 instances), and nausea (10 instances). In the late setting, 8 (6.4%) patients reported grade 1 toxicity, and 3 (2.4%) patients reported grade 2 side effects, in the form of cough (5 instances) and dyspnea (5 instances) after the irradiation of multiple lung lesions. No grade 3 or higher toxicity was reported both in the acute and late settings. Discussion In this analysis including 451 oligometastases in 136 patients treated with single course SABR, we found that tumor volume was a strong predictor of disease control and survival. While the number of treated metastases did not influence the patients’ outcome, in our experience we observed that an increasing tumor volume, analyzed both as continuous and with cut-offs values, was associated with inferior OS. The evidence regarding the importance of metastatic tumor volume as predictor of survival is still scarce despite the effort of the scientific oncologic community to look for predictive factors that can better define the burden of disease better compared to the number of metastases. Indeed, relevant results about tumor volume were observed for patients affected by brain metastases. In the study conducted by Baschnagel et al.[16] including 250 patients with 1 to 14 brain metastases all treated with radiosurgery, a TTV value ≥ 2 cm3 (p=0.008) was a stronger predictor of OS than the number of brain metastases (p=0.098). Also, Hirshman et al.[17] incorporated the cumulative intracranial tumor volume of metastatic melanoma patients into a prognostic scale that included also Karnofsky performance status and the number of brain metastases. In the recent publication by Kim et al.[18], two methods of evaluation for disease burden were compared, 3D tumor volume vs number of metastases. A total of 86 melanoma patients receiving immunotherapy were included and all metastatic lesions were contoured, most commonly lymph node, lung, and liver. The authors shown that the volume and the site of the metastatic disease were the important factor related to OS and an optimal cut-off of 37.9 cc was defined. In our study including different histologies, a value of 10 cc was the strongest predictor of OS (HR 2.88, p=0.002) while a 50 cc cut-off was associated with PFS (HR 1.93, p=0.002). Future prospective trials are needed to define the optimal cut-off values of tumor volume to distinguish between oligometastatic and polymetastatic disease, that should not be limited only by the number of metastases, especially if we consider that modern radiotherapy techniques allow us to irradiate even a large number of metastases safely and with ablative intent. Potentially, the risk of toxicity increases at the increase of the number of metastases treated with high-dose radiotherapy. This concern is reflected by the majority of the studies published on the oligometastatic disease. Chalkidou et al.[13] treated 1422 metastatic patients more commonly from prostate and colorectal cancer; about 75% of patients were treated on single lesion and less than 5% on 3 metastases. The well-known SABR-COMET trial[19] showed that the addition of SABR to the standard of care prolongs OS compared to the standard of care alone, with 5 years rate of 42.3% vs 17.7%, respectively. However, among 99 enrolled patients, 18% was treated on 3 lesions and only 2 and 3 patients received radiotherapy on 4 and 5 metastases simultaneously. According to an international survey to more than 1000 radiation oncologist[20], only 23% of respondents treats more than 3 oligometastases and even rare (6%) is the use of single course SABR to treat simultaneously 3 body lesions. Actually, the evidence regarding large volume extracranial disease treated with ablative radiotherapy is still scarce compared to the experiences published on brain disease. In the study conducted by Yamamoto et al.[21] radiosurgery was used to treat more than 1000 patients with up to 10 brain metastases; the study showed only 9% of patients reporting side effects and no difference in terms of survival between patients with 2-4 lesions vs 5-10 lesions. Interestingly, the authors used a maximum cumulative volume of 15.0 mL as inclusion criteria, confirming the importance of the volume over the number of lesions. For extracranial disease, indirect evidence comes from a prospective randomized phase II trial evaluating thermal ablation when added to systemic therapy in liver metastases from colorectal cancer. Among 119 patients, 70% had 3 or more metastases and the combined modality arm was associated with a reduced risk of death (HR 0.58, 95%CI 0.38 to 0.88, p=0.01)[22]. In a large study published by Yamamoto et al.[23] including 1378 lung oligometastases, the maximum tumour diameter correlated with LC (o=0.011) while this latter influenced patients’ survival. Inclusion criteria were, among the others, presence of 1 to 5 metastases, and BED10 75 Gy or more. Chmura et al. conducted a prospective phase I trial to evaluate the safety of SABR on patients affected by 3 to 4 oligometastases or 2 metastases near each other. A total of 39 were enrolled, with a median of 3 metastases treated per patient; median survival was not reached with a median follow-up of 22.6 months. No protocol-defined dose limiting toxicities were observed, and when examining all adverse events 8 grade 3 side effects, most likely related to the protocol therapy, were observed in 7 patients[24]. The on-going SABR-COMET-10[25] is enrolling patients affected by 4 to 10 oligometastases to elucidate the impact of SABR in this setting. However, a preliminary substudy of the trial was recently published showing that SABR planning was achievable without compromise in the majority of enrolled patients with only 3% of targets covered with a D95< 95% and less than 10% of plans did not meet conformality parameters[26]. Our study is characterized by several issue, including the retrospective nature of the analysis, the heterogeneity of the included patients in terms of primary tumors, disease characteristics and received concomitant systemic treatment. However, we do believe that our data adds relevant insights to the definition of the oligometastatic extracranial disease, which can guide in the personalization of the therapeutic choice. Conclusions In our study we demonstrated that tumor volume is a better predictor of survival than the number of lesions in patients affected by 3 to 5 oligometastases. In the absence of valid biomarkers, disease volume should be considered as a relevant factor for the therapeutic choice to evaluate which patients can benefit from SABR. Prospective trials are expected to confirm these results on larger population including patients with 1 -2 or more than 6 metastases, or in case of intracranial disease. Declarations All the authors declare no conflict of interest No fundings were used for the present study Keywords: oligometastatic; SBRT; SABR; stereotactic radiotherapy; oligometastases; multiple; radiosurgery; stereotactic ablative radiotherapy Data sharing statement: The data that support the findings of this study are available from the corresponding author, CF, upon reasonable request. Ciro Franzese: Conceptualization, Roles/Writing – original draft; Veronica Vernier: Data curation; Davide Franceschini: Data curation; Tiziana Comito: Supervision; Pierina Navarria: Supervision; Elena Clerici: Data curation; Maria Ausilia Teriaca: Data curation; Maria Massaro: Data curation; Luciana Di Cristina: Data curation; Beatrice Marini: Data curation; Carmela Galdieri: Supervision; Pietro Mancosu: Formal analysis; Stefano Tomatis: Formal analysis; Marta Scorsetti: Writing – review & editing References Hellman S, Weichselbaum RR. Oligometastases. Journal of Clinical Oncology 1995;13:8–10. https://doi.org/10.1200/jco.1995.13.1.8. Guckenberger M, Lievens Y, Bouma AB, Collette L, Dekker A, DeSouza NM, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol 2020;21:e18–28. https://doi.org/10.1016/S1470-2045(19)30718-1. Gomez DR, Blumenschein GR, Lee JJ, Hernandez M, Ye R, Camidge DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:1672–82. https://doi.org/10.1016/S1470-2045(16)30532-0. Iyengar P, Wardak Z, Gerber DE, Tumati V, Ahn C, Hughes RS, et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: A phase 2 randomized clinical trial. JAMA Oncol 2018;4. https://doi.org/10.1001/jamaoncol.2017.3501. Decaestecker K, De Meerleer G, Lambert B, Delrue L, Fonteyne V, Claeys T, et al. Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence. Radiation Oncology 2014;9:135. https://doi.org/10.1186/1748-717X-9-135. Gomez DR, Tang C, Zhang J, Blumenschein GR, Hernandez M, Jack Lee J, et al. Local consolidative therapy vs. Maintenance therapy or observation for patients with oligometastatic non–small-cell lung cancer: Long-term results of a multi-institutional, phase II, randomized study. Journal of Clinical Oncology 2019;37:1558–65. https://doi.org/10.1200/JCO.19.00201. Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. Journal of Clinical Oncology 2017:JCO.2017.75.485. https://doi.org/10.1200/JCO.2017.75.4853. Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol 2020;6:650–9. https://doi.org/10.1001/jamaoncol.2020.0147. Meyer E, Pasquier D, Bernadou G, Calais G, Maroun P, Bossi A, et al. Stereotactic radiation therapy in the strategy of treatment of metastatic renal cell carcinoma: A study of the Getug group. Eur J Cancer 2018;98:38–47. https://doi.org/10.1016/j.ejca.2018.04.008. Franzese C, Comito T, Toska E, Tozzi A, Clerici E, De Rose F, et al. Predictive factors for survival of oligometastatic colorectal cancer treated with Stereotactic body radiation therapy. Radiotherapy and Oncology 2018. https://doi.org/10.1016/j.radonc.2018.10.024. Ouyang W, Yu J, Nuerjiang S, Li Z, Wang D, Wang X, et al. Stereotactic body radiotherapy improves the survival of patients with oligometastatic non‐small cell lung cancer. Cancer Med 2019;8:4605–14. https://doi.org/10.1002/cam4.2366. Muldermans JL, Romak LB, Kwon ED, Park SS, Olivier KR. Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer. International Journal of Radiation Oncology*Biology*Physics 2016;95:696–702. https://doi.org/10.1016/j.ijrobp.2016.01.032. Chalkidou A, Macmillan T, Grzeda MT, Peacock J, Summers J, Eddy S, et al. Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study. Lancet Oncol 2021;22:98–106. https://doi.org/10.1016/S1470-2045(20)30537-4. Lievens Y, Guckenberger M, Gomez D, Hoyer M, Iyengar P, Kindts I, et al. Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document. Radiotherapy and Oncology 2020;148:157–66. https://doi.org/10.1016/j.radonc.2020.04.003. Park C, Papiez L ZS et al. Universal Survival Curve and Single Fraction Equivalent Dose: Useful Tools in Understanding Potency of Ablative Radiotherapy: In Regard to Parks et al. (Int J Radiat Oncol Biol Phys 2008;70:847–852). Int J Radiat Oncol Biol Phys 2008;70:847–52. https://doi.org/10.1016/j.ijrobp.2008.08.032. Baschnagel AM, Meyer KD, Chen PY, Krauss DJ, Olson RE, Pieper DR, et al. Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery. J Neurosurg 2013;119:1139–44. https://doi.org/10.3171/2013.7.JNS13431. Hirshman BR, Wilson BR, Ali MA, Schupper AJ, Proudfoot JA, Goetsch SJ, et al. Cumulative Intracranial Tumor Volume Augments the Prognostic Value of Diagnosis-Specific Graded Prognostic Assessment Model for Survival in Patients with Melanoma Cerebral Metastases. Neurosurgery 2018;83:237–44. https://doi.org/10.1093/neuros/nyx380. Kim J, Chang JS, Sung W, Kim JS, Kim TH, Choi SH, et al. A Comparison of 2 Disease Burden Assessment Methods (3D Volume Versus the Number of Lesions) for Prognostication of Survival in Metastatic Melanoma: Implications for the Characterization of Oligometastatic Disease. International Journal of Radiation Oncology*Biology*Physics 2022;114:883–91. https://doi.org/10.1016/j.ijrobp.2022.08.040. Palma DA, Olson R, Harrow S, Gaede S, Louie A V., Haasbeek C, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. Journal of Clinical Oncology 2020:JCO.20.00818. https://doi.org/10.1200/JCO.20.00818. Lewis SL, Porceddu S, Nakamura N, Palma DA, Lo SS, Hoskin P, et al. Definitive Stereotactic Body Radiotherapy (SBRT) for Extracranial Oligometastases. Am J Clin Oncol 2017;40:418–22. https://doi.org/10.1097/COC.0000000000000169. Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15:387–95. https://doi.org/10.1016/S1470-2045(14)70061-0. Ruers T, van Coevorden F, Punt CJA, Pierie J-PEN, Borel-Rinkes I, Ledermann JA, et al. Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial. JNCI: Journal of the National Cancer Institute 2017;109. https://doi.org/10.1093/jnci/djx015. Yamamoto T, Niibe Y, Aoki M, Shintani T, Yamada K, Kobayashi M, et al. Analyses of the local control of pulmonary Oligometastases after stereotactic body radiotherapy and the impact of local control on survival. BMC Cancer 2020;20:997. https://doi.org/10.1186/s12885-020-07514-9. Chmura S, Winter KA, Robinson C, Pisansky TM, Borges V, Al-Hallaq H, et al. Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases. JAMA Oncol 2021;7:845. https://doi.org/10.1001/jamaoncol.2021.0687. Palma DA, Olson R, Harrow S, Correa RJM, Schneiders F, Haasbeek CJA, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial. BMC Cancer 2019;19:816. https://doi.org/10.1186/s12885-019-5977-6. Ashram S, Bahig H, Barry A, Blanchette D, Celinksi A, Chung P, et al. Planning Trade-offs for SABR in Patients With 4 to 10 Metastases: A Substudy of the SABR-COMET-10 Randomized Trial. International Journal of Radiation Oncology*Biology*Physics 2022;114:1011–5. https://doi.org/10.1016/j.ijrobp.2022.05.035. Tables Table 1 Patients and disease characteristics N. patients 136 N. oligometastases 450 Age, median (range) 67.8 (28.0 – 87.1) Gender Male Female 80 (58.8) 56 (41.2) Performance status 0 1 2 91 (66.9) 36 (26.5) 9 (6.6) Primary tumor Colorectal Lung Prostate Breast Others 60 (44.1) 16 (11.8) 8 (5.9) 7 (5.1) 45 (33.1) Histology Adenocarcinoma Non-adenocarcinoma 110 (80.8) 26 (19.2) Disease free interval, median (range) 14.1 months (0 – 222.1) Timing of metastases Synchronous Metachronous 39 (28.7) 97 (71.3) ESTRO-EORTC classification 1 De novo sincrono 2 De novo metacrono oligorecurrence 3 De novo metacrono oligoprogression 4 Repeat oligorecurrence 7 Induced oligorecurrence 8 Induced oligopersistence 9 Induced oligoprogression 6 (4.4) 20 (14.7) 2 (1.5) 25 (18.4) 59 (43.4) 16 (11.8) 8 (5.9) Previous local treatment No Yes 82 (60.3) 54 (39.7) Previous systemic therapy No 1 line 2 lines 3 or more lines 36 (26.5) 43 (31.6) 35 (25.7) 22 (16.2) Treated metastases 3 4 5 102 (75.0) 26 (19.1) 8 (5.9) Total tumor volume in cc, median (range) 19.1 (0.6 – 245.1) Treated site Lung Liver Lymph node Lung and lymph node Lung and liver Liver and lymph node Other (adrenal glands, pancreas, spine and non-spinal bone) 47 (34.6) 31 (22.8) 19 (14.0) 11 (8.1) 10 (7.3) 7 (5.1) 11 (8.1) Treated organs 1 2 3 97 (71.3) 36 (26.5) 3 (2.2) Presence of extra-target disease No Yes 119 (87.5) 17 (12.5) Concomitant systemic therapy No Yes Anti-EGFR Chemotherapy Hormonal therapy / New generation hormonal therapy TKI Immunotherapy 102 (75.0) 34 (25.0) 2 11 9 6 6 Dose in terms EQD2, median (range) - EQD2 50 Gy to 70 Gy - EQD2 > 70 Gy to 100 Gy - EQD2 > 100 Gy 83.3 (37.5 – 218.7) 18 (13.2) 39 (28.7) 64 (47.1) 15 (11.0) Table 2 Univariate and multivariable analysis for Overall survival and Progression free survival. Values in bold are statistically significant. Univariate analysis Overall survival Progression free survival HR 95%CI P value HR 95%CI P value Age 1.03 1.01 – 1.05 0.003 1.01 0.99 – 1.02 0.058 Gender 1.09 0.68 – 1.74 0.709 0.99 0.69 – 1.43 0.977 Perfomance status, continuous 1.87 1.33 – 2.61 0.000 1.31 0.99 – 1.73 0.053 Primary tumor, colorectal vs other 0.74 0.47 – 1.17 0.206 0.77 0.54 – 1.11 0.167 Disease free interval, months 0.99 0.99 – 1.00 0.868 0.99 0.99 – 1.00 0.438 Synchronous vs metachronous 0.73 0.45 – 1.20 0.226 0.82 0.55 – 1.22 0.351 Previous LAT 0.79 0.49 – 1.27 0.349 1.22 0.85 – 1.75 0.271 Number treated mets: continuous 0.98 0.72 – 1.33 0.907 0.97 0.72 – 1.30 0.863 3 vs ≥ 4 0.97 0.57 – 1.64 0.925 1.00 0.66 – 1.50 0.998 ≤ 4 vs 5 0.99 0.39 – 2.46 0.988 0.86 0.42 – 1.76 0.686 Number treated organs, continuous 1.62 1.08 – 2.45 0.019 1.49 1.08 – 2.06 0.013 Treated site, Lung vs other 1.04 0.65 – 1.64 0.860 1.14 0.79 – 1.64 0.461 Treated site, liver vs other 0.65 0.41 – 1.04 0.076 0.67 0.46 – 0.97 0.036 Extratarget disease 0.83 0.36 – 1.93 0.673 1.37 0.81 – 2.33 0.235 Minimum EQD2: continuous 0.98 0.97 – 0.99 0.024 0.99 0.98 – 0.99 0.031 ≤ 50 vs > 50 Gy 0.46 0.24 – 0.90 0.023 0.56 0.32 – 0.97 0.040 ≤ 70 vs > 70 Gy 0.53 0.33 – 0.85 0.009 0.65 0.45 – 0.93 0.020 ≤ 100 vs > 100 Gy 1.02 0.54 – 1.89 0.945 0.94 0.55 – 1.59 0.822 Total tumor volume: continuous 1.00 1.00 – 1.01 0.000 1.00 1.00 – 1.01 0.000 ≤ 5 vs > 5 cc 2.31 1.00 – 5.35 0.050 1.61 0.90 – 2.89 0.105 ≤ 10 vs > 10 cc 2.88 1.47 – 5.63 0.002 1.44 0.95 – 2.20 0.083 ≤ 50 vs > 50 cc 2.83 1.70 – 4.69 0.000 1.93 1.26 – 2.96 0.002 Multivariable analysis Overall survival Progression free survival Age 1.01 0.99 – 1.04 0.124 - - - Performance status 1.41 0.93 – 2.13 0.101 - - - Number treated organs 1.30 0.86 – 1.95 0.208 1.29 0.93 – 1.80 0.118 Treated site, liver vs other - - - 0.72 0.48 – 1.07 0.107 Minimum EQD2, ≤ 50 vs > 50 Gy 0.54 0.27 – 1.05 0.073 0.57 0.32 – 1.01 0.055 Total tumor volume, ≤ 10 vs > 10 cc 2.38 1.18 – 4.78 0.014 - - - Total tumor volume, ≤ 50 vs > 50 cc - - - 1.63 1.05 – 2.54 0.028 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 06 Jun, 2023 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted Editorial decision: Accepted 02 Jun, 2023 Reviewers agreed at journal 08 May, 2023 Reviewers agreed at journal 27 Apr, 2023 Reviewers invited by journal 21 Apr, 2023 Editor assigned by journal 21 Apr, 2023 Submission checks completed at journal 20 Apr, 2023 First submitted to journal 19 Apr, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2835255","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":193796695,"identity":"f5c28034-ea3a-4454-a0e0-bab09ca7d85f","order_by":0,"name":"Ciro Franzese","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYDACZhBhA+NVHICI8BDUkgbjnSFGCwOyFsa2AxAGPi387bwPHzAk3JM35z98+MPHeXcSt7NzJz54w2CT2IBDi8RhdmMDhoRiw50Nx9IkZ257lrizmXez4RyGNJxaDJjZ2CQYfyQwbjjYY8bMu+1w4obDvNukeRgO49fCkJBgv+Ew/+fPf+eAtWz/zcPwn6CWxA3HeBikGRsgtjDzMBzA4xc2ZoOEhITkDWfYzCR7jh02BmrZLDnHINkYlxb+/mOMDz4kJNhuOH/48YcfNYdlN5w/u/HDmwo7WVxawCABi4PxqR8Fo2AUjIJRQAgAAPSyWUpNbXCaAAAAAElFTkSuQmCC","orcid":"","institution":"Humanitas University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ciro","middleName":"","lastName":"Franzese","suffix":""},{"id":193796696,"identity":"744f2aff-daf9-4848-9922-4f6a125e599c","order_by":1,"name":"Veronica Vernier","email":"","orcid":"","institution":"Humanitas University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Veronica","middleName":"","lastName":"Vernier","suffix":""},{"id":193796697,"identity":"7d2db5ad-b776-4b68-acc5-5f48076e5367","order_by":2,"name":"Davide Franceschini","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Davide","middleName":"","lastName":"Franceschini","suffix":""},{"id":193796698,"identity":"7001b21b-1d7f-46b0-b55f-2548dc3c52ec","order_by":3,"name":"Tiziana Comito","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tiziana","middleName":"","lastName":"Comito","suffix":""},{"id":193796699,"identity":"208c796f-99f9-477e-8c5a-83b585787771","order_by":4,"name":"Pierina Navarria","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pierina","middleName":"","lastName":"Navarria","suffix":""},{"id":193796700,"identity":"ce92becb-0971-4f21-92cb-bd16a0f6e854","order_by":5,"name":"Elena Clerici","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Clerici","suffix":""},{"id":193796701,"identity":"8d01e5db-5cf1-472e-8b07-8e585a8e8550","order_by":6,"name":"Maria Ausilia Teriaca","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Ausilia","lastName":"Teriaca","suffix":""},{"id":193796702,"identity":"52e8ecd1-4fe6-42f0-a1dd-1ceda0c955fa","order_by":7,"name":"Maria Massaro","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Massaro","suffix":""},{"id":193796703,"identity":"ecf5f345-71c0-40d8-909a-db07b33a43b4","order_by":8,"name":"Luciana Cristina","email":"","orcid":"","institution":"Humanitas University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Luciana","middleName":"","lastName":"Cristina","suffix":""},{"id":193796704,"identity":"9d541907-ba60-4b7a-8015-ca77dc8f53b3","order_by":9,"name":"Beatrice Marini","email":"","orcid":"","institution":"Humanitas University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Beatrice","middleName":"","lastName":"Marini","suffix":""},{"id":193796705,"identity":"dd6980c2-e454-4589-9821-8ad9007c94cd","order_by":10,"name":"Carmela Galdieri","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carmela","middleName":"","lastName":"Galdieri","suffix":""},{"id":193796706,"identity":"b160fd1f-a782-4fb6-ab03-a73a0504c697","order_by":11,"name":"Pietro Mancosu","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pietro","middleName":"","lastName":"Mancosu","suffix":""},{"id":193796707,"identity":"6784a51a-9511-49c3-96e8-a145a0d4310d","order_by":12,"name":"Stefano Tomatis","email":"","orcid":"","institution":"IRCCS Humanitas Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Tomatis","suffix":""},{"id":193796708,"identity":"9339e5fb-3499-4938-a380-81add3117c98","order_by":13,"name":"Marta Scorsetti","email":"","orcid":"","institution":"Humanitas University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"Scorsetti","suffix":""}],"badges":[],"createdAt":"2023-04-19 07:29:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2835255/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2835255/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00432-023-04964-z","type":"published","date":"2023-06-06T21:07:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":36342344,"identity":"971a58ef-5627-4539-9780-5ce4f1d4eca5","added_by":"auto","created_at":"2023-04-26 19:24:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":320873,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves for Overall survival of all the population and stratified according to tumor volume.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2835255/v1/a8ed63e552669ea0a37e486a.jpg"},{"id":36342345,"identity":"69fb1704-9548-487b-ac55-c069530017e2","added_by":"auto","created_at":"2023-04-26 19:24:25","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":340369,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves for Progression Free Survival of all the population and stratified according to tumor volume.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2835255/v1/8ceb0ddaf72ddfe3d1a76259.jpg"},{"id":44734913,"identity":"4a27ca42-8e6c-4d71-8a71-dc40c7727d97","added_by":"auto","created_at":"2023-10-16 22:22:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":502798,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2835255/v1/9704f293-f0be-4002-8a92-aa26c221868c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Total tumor volume as a predictor of survival in patients with multiple oligometastases treated with stereotactic ablative radiotherapy (SABR)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe oligometastatic state was first defined in 1995 as an intermediate state between localized and widespread diffuse disease[1]. However, it is now recognized as a heterogeneous setting that includes patients who differ from each other in several characteristics, including timing of appearance of metastases and the extent of disease. Recently, the ESTRO-EORTC consensus recommendation established a classification of these patients into subcategories based on 17 disease characterization factors and 5 different questions[2]. Stereotactic ablative radiotherapy (SABR) emerged in the last years as an effective local treatment for patients with a limited number of metastases. For example, Gomez et al.[3] evaluated the impact of local consolidative therapy in addition to standard of care in patients with 3 or fewer metastases from non-small cell lung cancer (NSCLC), showing a median overall survival (OS) of 41.2 months in the local treatment arm vs 17.0 months in the standard of care arm (p=0.017). A significant benefit was also demonstrated by Iyengar et al.[4] in a prospective trial that included oligometastatic NSCLC patients with no more than 3 lesions in the liver or lung.\u003c/p\u003e\u003cp\u003eCurrently, the oligometastatic state is defined only by the maximum number of metastases visible on diagnostic imaging, typically ranging from 1 to 3 lesions[5\u0026ndash;8], as there are no validated biomarkers to confirm the existence of limited burden of disease. Nevertheless, delivering SABR in patients with multiple metastases remains a challenge from both the clinical and technical perspectives, and only a few patients with 3 or more lesions have been included in most studies on the oligometastatic disease [9\u0026ndash;13]. Indeed, it is matter of debate whether the limit to metastases\u0026rsquo; ablation should be numerical or related to the technical feasibility and the risk of toxicity. In the document by Lievens et al.[14] a consensus was reached on the possibility of safely delivering curative intent metastasis-directed radiotherapy instead of limiting the maximum number of oligometastases.\u003c/p\u003e\u003cp\u003eIn the present study, we aimed to evaluate survival and toxicity of a large sample of patients affected by multiple oligometastases treated with single course SABR, and to evaluate the impact of tumor volume on patients\u0026rsquo; outcome.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eWe included in this retrospective analysis patients treated in our Institution with a single course of SABR on 3 to 5 extracranial oligometastases from any solid tumors. Patients with brain metastases or malignant pleural effusion were excluded from the analysis. Each case was discussed with a multidisciplinary board to reach consensus on the optimal therapeutic strategy. The local ethic committee approved the analysis. The study was conducted in accordance with the Good Clinical Practice guidelines, the ethical principles of the Declaration of Helsinki and local regulations. All the patients were simulated with a CT scan, registered with MRI or PET scan when available. All patients were positioned supine and immobilized with a thermoplastic mask. The clinical target volume (CTV) was equal to the gross tumor volume (GTV) and an isotropic margin of 3 - 10 mm, depending on disease site and dimensions, was added to the CTV to obtain the planning target volume (PTV). All patients were treated with the volumetric modulated arc therapy (VMAT) technique. The patient’s position was evaluated daily with cone-beam CT imaging before each treatment session. To compare the different treatment schedule, the biological effective dose (BED) was calculated. The linear quadratic model used for calculation was \u003cspan lang=\"IT\"\u003e[15]\u003c/span\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n\u003cp\u003eBED was calculated with a α/β of 10.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Equivalent dose in 2Gy fractions (EQD2) was calculated with the following formula:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n\u003cp\u003eClinical and radiological evaluation with CT or MRI scan was carried out every 3 months after SABR. The tumor response was classified according to the European Organization for Research and Treatment of Cancer Response Evaluation Criteria In Solid Tumours (EORTC-RECIST) criteria version 1.16.\u003c/p\u003e\n\u003cp\u003eEnd-points of the analysis were OS, progression free survival (PFS), local control (LC) and pattern of toxicity. The OS was calculated from SABR to death from any cause or last follow-up. The PFS was defined as the time from treatment to in-field or out-field progression or death from any cause. The LC was calculated from SBRT to first in-field progression, death from any cause or last-follow-up. Univariate analysis was carried out using the Log-rank test and Cox proportional hazards regression was used to estimate hazard ratios for the potential risk factors. Variables with a value 0.05 at univariate test were selected for the multivariable Cox regression analysis carried out to evaluate the association between clinical factors and survival. Statistical calculations were carried out using STATA, version 15.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe included a total of 136 patients treated with SABR from 2012 to 2020 on 451 oligometastases. Patients\u0026rsquo; and disease\u0026rsquo;s characteristics are described in Table 1. Median age was 67.8 years (range 28.0 \u0026ndash; 87.1), and majority of patients was male (58.8%). Most common primary tumor was colorectal cancer (60, 44.1%) followed by lung cancer (16, 11.8) and prostate cancer (8, 5.9%). Median disease-free interval (DFI) calculated from diagnosis of primary tumor to first appearance of metastases was 14.1 months (range 0 \u0026ndash; 222.1). A total of 39 (28.7%) patients had synchronous metastatic disease. According to ESTRO-EORTC consensus, majority of patients was classified as induced oligorecurrence (25, 18.38%), and repeat oligorecurrence (59, 43.38%). Fifty-four (39.7%) patients had previous local treatment before SABR, and 22 (16.2%) patients received 3 or more lines of systemic therapies before treatment. A total of 3, 4 or 5 lesions were simultaneously treated in 102 (75.0%), 26 (19.1%), and 8 (5.9%) patients. Median total tumor volume (TTV) was 19.1 cc with a range of \u0026nbsp;0.6 to 245.1 cc. Site of metastases treated with SBRT were lung, liver, lymph node, pancreas, adrenal gland, and bones, both spine and non-spine. Multiple lesions in the lung were treated in 47 (34.6%) patients, and in the liver in 31 (22.8%) cases. Two or three organs were treated simultaneously in 36 (26.5%) and 3 (2.2%) patients, respectively. In 17 (12.5%) patients was present extra-target disease as non-irradiated metastases already in control by the on-going systemic therapy. Median EQD2 was 83.3 Gy with a range from 37.5 to 218.7 Gy. An EQD2 of 70 \u0026ndash; 100 Gy was adopted in 64 (47.1%) patients and \u0026gt; 100 Gy in 15 (11.0%) patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWith a median follow-up of 25.0 months, rates of OS at 1 and 3 years were 88.4% (95%CI 81.5 \u0026ndash; 92.8) and 50.2% (95%CI 40.5 \u0026ndash; 59.2). Results of univariate analysis are reported in Table 2. On univariate analysis, higher age, higher Eastern Cooperative Oncology Group (ECOG) performance status (PS), lower EQD2 and higher TTV were associated with worse OS. An EQD2 \u0026gt; 50 Gy and TTV\u0026nbsp;\u0026le;\u0026nbsp;10 cc were associated with the lowest risk of death. At multivariable analysis, however only increasing TTV was predictive of worse OS with an HR of 2.37 (95%CI 1.18 \u0026ndash; 4.78, p=0.014). Figure 1 illustrate Kaplan-Meier curves for OS of the whole population and according to TTV. Median OS was 80.6 months if tumor volume was\u0026nbsp;\u0026le;\u0026nbsp;10 cc\u003csup\u003e\u0026nbsp;\u003c/sup\u003e (1 and 3 years OS rate 93.6% and 77.5%, respectively), and 31.1 months if TTV was higher than 10 cc (1 and 3 years OS rate 86.7% and 42.3%, respectively). We didn\u0026rsquo;t observe a correlation neither between LC and OS (p=0.216) nor LC and PFS (p=0.549). Median PFS of the whole group was 8.06 months. Rates of PFS at 1 and 3 years were 34.8% (95%CI 26.9 \u0026ndash; 42.9) and 6.5% (95%CI 2.9 \u0026ndash; 12.1) as shown in Figure 2. At univariate analysis, number of treated organs, non-liver metastases, minimum EQD2 and TTV were significantly associated with PFS. At multivariable analysis, only TTV remained a negative predictive factor for PFS (HR 1.63, 95%CI 1.05 \u0026ndash; 2.54; p=0.028). \u0026nbsp;A total of 47 (38.2%) patients intensified, switched, or activated systemic therapy after SABR. At first progression after SABR, 96 (71.6%) patients had 5 or less metastatic progressions, while 38 (28.4%) patients were diagnosed with poliprogressive disease. Globally a total of 50 (36.8%) patients had polymetastatic progression during follow-up. Sixty-seven (53.2%) patients received a second course of local ablative treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLocal progression of the treated metastases was observed in 80 (17.7%) lesions and 42 (30.9%) patients with a median LC not achieved. Rates of LC at 1 and 3 years analyzed at lesions\u0026rsquo; level were 89.3% (95%CI 85.9 \u0026ndash; 91.9) and 76.5% (95%CI 71.2 \u0026ndash; 80.4). At univariate analysis, a volume larger than 50 cc was associated with lower LC (HR 2.38, 1.47 \u0026ndash; 3.84; p=0.000) while the use of concomitant systemic therapies was a positive predictive factor (HR 0.26, 95%CI 0.12 \u0026ndash; 0.58; p=0.001). There was a trend of significance for the dose in terms of EQD2 (HR 0.99, 95%CI 0.98 \u0026ndash; 1.00; p=0.058). At multivariable analysis, the volume (HR 1.92, 95%CI 1.18 \u0026ndash; 3.12; p=0.009), concomitant treatment (HR 0.28, 95%CI 0.13 \u0026ndash; 0.62; p=0.02) and the dose (HR 0.99, 95%CI 0.98 \u0026ndash; 0.99; p=0.049) were statistically significant for LC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe made a subgroup analysis according to TTV to evaluate the impact of dose on defined population. For patients with TTV\u0026nbsp;\u0026le; 10 cc, the minimum EQD2 was not correlated with OS (HR 0.67, 95%CI 0.23 \u0026ndash; 1.99; p=0.478). For patients with TTV \u0026gt; 10 cc, the increasing EQD2 was associated with longer survival (HR 0.98, 95%CI 0.97 \u0026ndash; 0.99; p=0.018), with a median OS of 21.2 months for EQD2 \u0026le; 50 Gy and 31.9 months for EQD2 \u0026gt; 50. Nevertheless, the dose was not correlated with PFS in both TTV \u0026le; 50 cc (HR 0.99, 95%CI 0.98 \u0026ndash; 1.00; p=0.066) and \u0026gt; 50 cc (HR 0.99, 95%CI 0.98 \u0026ndash; 1.00; p=0.319).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn terms of toxicity, in the acute setting we observed 26 (21.0%) patients and 11 (8.9%) patients reporting grade 1 and grade 2 side effect, respectively. Most commonly acute toxicities included fatigue (11 instances), pain (11 instances), and nausea (10 instances). In the late setting, 8 (6.4%) patients reported grade 1 toxicity, and 3 (2.4%) patients reported grade 2 side effects, in the form of cough (5 instances) and dyspnea (5 instances) after the irradiation of multiple lung lesions. No grade 3 or higher toxicity was reported both in the acute and late settings.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this analysis including 451 oligometastases in 136 patients treated with single course SABR, we found that tumor volume was a strong predictor of disease control and survival. While the number of treated metastases did not influence the patients\u0026rsquo; outcome, in our experience we observed that an increasing tumor volume, analyzed both as continuous and with cut-offs values, was associated with inferior OS. The evidence regarding the importance of metastatic tumor volume as predictor of survival is still scarce despite the effort of the scientific oncologic community to look for predictive factors that can better define the burden of disease better compared to the number of metastases. Indeed, relevant results about tumor volume were observed for patients affected by brain metastases. In the study conducted by Baschnagel et al.[16] including 250 patients with 1 to 14 brain metastases all treated with radiosurgery, a TTV value \u0026ge; 2 cm3 (p=0.008) was a stronger predictor of OS than the number of brain metastases (p=0.098). Also, Hirshman et al.[17] incorporated the cumulative intracranial tumor volume of metastatic melanoma patients into a prognostic scale that included also Karnofsky performance status and the number of brain metastases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the recent publication by Kim et al.[18], two methods of evaluation for disease burden were compared, 3D tumor volume vs number of metastases. A total of 86 melanoma patients receiving immunotherapy were included and all metastatic lesions were contoured, most commonly lymph node, lung, and liver. The authors shown that the volume and the site of the metastatic disease were the important factor related to OS and an optimal cut-off of 37.9 cc was defined. In our study including different histologies, a value of 10 cc was the strongest predictor of OS (HR 2.88, p=0.002) while a 50 cc cut-off was associated with PFS (HR 1.93, p=0.002).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFuture prospective trials are needed to define the optimal cut-off values of tumor volume to distinguish between oligometastatic and polymetastatic disease, that should not be limited only by the number of metastases, especially if we consider that modern radiotherapy techniques allow us to irradiate even a large number of metastases safely and with ablative intent. Potentially, the risk of toxicity increases at the increase of the number of metastases treated with high-dose radiotherapy. This concern is reflected by the majority of the studies published on the oligometastatic disease. Chalkidou et al.[13] treated 1422 metastatic patients more commonly from prostate and colorectal cancer; about 75% of patients were treated on single lesion and less than 5% on 3 metastases. The well-known SABR-COMET trial[19] showed that the addition of SABR to the standard of care prolongs OS compared to the standard of care alone, with 5 years rate of 42.3% vs 17.7%, respectively. However, among 99 enrolled patients, 18% was treated on 3 lesions and only 2 and 3 patients received radiotherapy on 4 and 5 metastases simultaneously. \u0026nbsp;According to an international survey to more than 1000 radiation oncologist[20], only 23% of respondents treats more than 3 oligometastases and even rare (6%) is the use of single course SABR to treat simultaneously 3 body lesions.\u003c/p\u003e\n\u003cp\u003eActually, the evidence regarding large volume extracranial disease treated with ablative radiotherapy is still scarce compared to the experiences published on brain disease. In the study conducted by Yamamoto et al.[21] radiosurgery was used to treat more than 1000 patients with up to 10 brain metastases; the study showed only 9% of patients reporting side effects and no difference in terms of survival between patients with 2-4 lesions vs 5-10 lesions. Interestingly, the authors used a maximum cumulative volume of 15.0 mL as inclusion criteria, confirming the importance of the volume over the number of lesions. For extracranial disease, indirect evidence comes from a prospective randomized phase II trial evaluating thermal ablation when added to systemic therapy in liver metastases from colorectal cancer. Among 119 patients, 70% had 3 or more metastases and the combined modality arm was associated with a reduced risk of death (HR 0.58, 95%CI 0.38 to 0.88, p=0.01)[22]. \u0026nbsp;In a large study published by Yamamoto et al.[23] including 1378 lung oligometastases, the maximum tumour diameter correlated with LC (o=0.011) while this latter influenced patients\u0026rsquo; survival. Inclusion criteria were, among the others, presence of 1 to 5 metastases, and BED10 75 Gy or more. Chmura et al. conducted a prospective phase I trial to evaluate the safety of SABR on patients affected by 3 to 4 oligometastases or 2 metastases near each other. A total of 39 were enrolled, with a median of 3 metastases treated per patient; median survival was not reached with a median follow-up of 22.6 months. No protocol-defined dose limiting toxicities were observed, and when examining all adverse events 8 grade 3 side effects, most likely related to the protocol therapy, were observed in 7 patients[24]. The on-going SABR-COMET-10[25] is enrolling patients affected by 4 to 10 oligometastases to elucidate the impact of SABR in this setting. However, a preliminary substudy of the trial was recently published showing that SABR planning was achievable without compromise in the majority of enrolled patients with only 3% of targets covered with a D95\u0026lt; 95% and less than 10% of plans did not meet conformality parameters[26].\u003c/p\u003e\n\u003cp\u003eOur study is characterized by several issue, including the retrospective nature of the analysis, the heterogeneity of the included patients in terms of primary tumors, disease characteristics and received concomitant systemic treatment. However, we do believe that our data adds relevant insights to the definition of the oligometastatic extracranial disease, which can guide in the personalization of the therapeutic choice.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn our study we demonstrated that tumor volume is a better predictor of survival than the number of lesions in patients affected by 3 to 5 oligometastases. In the absence of valid biomarkers, disease volume should be considered as a relevant factor for the therapeutic choice to evaluate which patients can benefit from SABR. Prospective trials are expected to confirm these results on larger population including patients with 1 -2 or more than 6 metastases, or in case of intracranial disease.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAll the authors declare no conflict of interest\u003c/p\u003e\n\u003cp\u003eNo fundings were used for the present study\u003c/p\u003e\n\u003cp\u003eKeywords: oligometastatic; SBRT; SABR; stereotactic radiotherapy; oligometastases; multiple; radiosurgery; stereotactic ablative radiotherapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData sharing statement: The data that support the findings of this study are available from the corresponding author, CF, upon reasonable request.\u003c/p\u003e\n\u003cp\u003eCiro Franzese: Conceptualization, Roles/Writing \u0026ndash; original draft; \u0026nbsp;Veronica Vernier: Data curation; \u0026nbsp;Davide Franceschini: Data curation; \u0026nbsp;Tiziana Comito: Supervision; \u0026nbsp;Pierina Navarria: Supervision; Elena Clerici: Data curation; \u0026nbsp;Maria Ausilia Teriaca: Data curation; \u0026nbsp;Maria Massaro: Data curation; \u0026nbsp;Luciana Di Cristina: Data curation; \u0026nbsp;Beatrice Marini: Data curation; \u0026nbsp;Carmela Galdieri: Supervision; Pietro Mancosu: Formal analysis; \u0026nbsp;Stefano Tomatis: Formal analysis; \u0026nbsp;Marta Scorsetti: Writing \u0026ndash; review \u0026amp; editing\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHellman S, Weichselbaum RR. Oligometastases. Journal of Clinical Oncology 1995;13:8\u0026ndash;10. https://doi.org/10.1200/jco.1995.13.1.8.\u003c/li\u003e\n\u003cli\u003eGuckenberger M, Lievens Y, Bouma AB, Collette L, Dekker A, DeSouza NM, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol 2020;21:e18\u0026ndash;28. https://doi.org/10.1016/S1470-2045(19)30718-1.\u003c/li\u003e\n\u003cli\u003eGomez DR, Blumenschein GR, Lee JJ, Hernandez M, Ye R, Camidge DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:1672\u0026ndash;82. https://doi.org/10.1016/S1470-2045(16)30532-0.\u003c/li\u003e\n\u003cli\u003eIyengar P, Wardak Z, Gerber DE, Tumati V, Ahn C, Hughes RS, et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: A phase 2 randomized clinical trial. JAMA Oncol 2018;4. https://doi.org/10.1001/jamaoncol.2017.3501.\u003c/li\u003e\n\u003cli\u003eDecaestecker K, De Meerleer G, Lambert B, Delrue L, Fonteyne V, Claeys T, et al. Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence. Radiation Oncology 2014;9:135. https://doi.org/10.1186/1748-717X-9-135.\u003c/li\u003e\n\u003cli\u003eGomez DR, Tang C, Zhang J, Blumenschein GR, Hernandez M, Jack Lee J, et al. Local consolidative therapy vs. Maintenance therapy or observation for patients with oligometastatic non\u0026ndash;small-cell lung cancer: Long-term results of a multi-institutional, phase II, randomized study. Journal of Clinical Oncology 2019;37:1558\u0026ndash;65. https://doi.org/10.1200/JCO.19.00201.\u003c/li\u003e\n\u003cli\u003eOst P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. Journal of Clinical Oncology 2017:JCO.2017.75.485. https://doi.org/10.1200/JCO.2017.75.4853.\u003c/li\u003e\n\u003cli\u003ePhillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol 2020;6:650\u0026ndash;9. https://doi.org/10.1001/jamaoncol.2020.0147.\u003c/li\u003e\n\u003cli\u003eMeyer E, Pasquier D, Bernadou G, Calais G, Maroun P, Bossi A, et al. Stereotactic radiation therapy in the strategy of treatment of metastatic renal cell carcinoma: A study of the Getug group. Eur J Cancer 2018;98:38\u0026ndash;47. https://doi.org/10.1016/j.ejca.2018.04.008.\u003c/li\u003e\n\u003cli\u003e Franzese C, Comito T, Toska E, Tozzi A, Clerici E, De Rose F, et al. Predictive factors for survival of oligometastatic colorectal cancer treated with Stereotactic body radiation therapy. Radiotherapy and Oncology 2018. https://doi.org/10.1016/j.radonc.2018.10.024.\u003c/li\u003e\n\u003cli\u003e Ouyang W, Yu J, Nuerjiang S, Li Z, Wang D, Wang X, et al. Stereotactic body radiotherapy improves the survival of patients with oligometastatic non‐small cell lung cancer. Cancer Med 2019;8:4605\u0026ndash;14. https://doi.org/10.1002/cam4.2366.\u003c/li\u003e\n\u003cli\u003e Muldermans JL, Romak LB, Kwon ED, Park SS, Olivier KR. Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer. International Journal of Radiation Oncology*Biology*Physics 2016;95:696\u0026ndash;702. https://doi.org/10.1016/j.ijrobp.2016.01.032.\u003c/li\u003e\n\u003cli\u003e Chalkidou A, Macmillan T, Grzeda MT, Peacock J, Summers J, Eddy S, et al. Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study. Lancet Oncol 2021;22:98\u0026ndash;106. https://doi.org/10.1016/S1470-2045(20)30537-4.\u003c/li\u003e\n\u003cli\u003e Lievens Y, Guckenberger M, Gomez D, Hoyer M, Iyengar P, Kindts I, et al. Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document. Radiotherapy and Oncology 2020;148:157\u0026ndash;66. https://doi.org/10.1016/j.radonc.2020.04.003.\u003c/li\u003e\n\u003cli\u003e Park C, Papiez L ZS et al. Universal Survival Curve and Single Fraction Equivalent Dose: Useful Tools in Understanding Potency of Ablative Radiotherapy: In Regard to Parks et al. (Int J Radiat Oncol Biol Phys 2008;70:847\u0026ndash;852). Int J Radiat Oncol Biol Phys 2008;70:847\u0026ndash;52. https://doi.org/10.1016/j.ijrobp.2008.08.032.\u003c/li\u003e\n\u003cli\u003e Baschnagel AM, Meyer KD, Chen PY, Krauss DJ, Olson RE, Pieper DR, et al. Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery. J Neurosurg 2013;119:1139\u0026ndash;44. https://doi.org/10.3171/2013.7.JNS13431.\u003c/li\u003e\n\u003cli\u003e Hirshman BR, Wilson BR, Ali MA, Schupper AJ, Proudfoot JA, Goetsch SJ, et al. Cumulative Intracranial Tumor Volume Augments the Prognostic Value of Diagnosis-Specific Graded Prognostic Assessment Model for Survival in Patients with Melanoma Cerebral Metastases. Neurosurgery 2018;83:237\u0026ndash;44. https://doi.org/10.1093/neuros/nyx380.\u003c/li\u003e\n\u003cli\u003e Kim J, Chang JS, Sung W, Kim JS, Kim TH, Choi SH, et al. A Comparison of 2 Disease Burden Assessment Methods (3D Volume Versus the Number of Lesions) for Prognostication of Survival in Metastatic Melanoma: Implications for the Characterization of Oligometastatic Disease. International Journal of Radiation Oncology*Biology*Physics 2022;114:883\u0026ndash;91. https://doi.org/10.1016/j.ijrobp.2022.08.040.\u003c/li\u003e\n\u003cli\u003e Palma DA, Olson R, Harrow S, Gaede S, Louie A V., Haasbeek C, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. Journal of Clinical Oncology 2020:JCO.20.00818. https://doi.org/10.1200/JCO.20.00818.\u003c/li\u003e\n\u003cli\u003e Lewis SL, Porceddu S, Nakamura N, Palma DA, Lo SS, Hoskin P, et al. Definitive Stereotactic Body Radiotherapy (SBRT) for Extracranial Oligometastases. Am J Clin Oncol 2017;40:418\u0026ndash;22. https://doi.org/10.1097/COC.0000000000000169.\u003c/li\u003e\n\u003cli\u003e Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15:387\u0026ndash;95. https://doi.org/10.1016/S1470-2045(14)70061-0.\u003c/li\u003e\n\u003cli\u003e Ruers T, van Coevorden F, Punt CJA, Pierie J-PEN, Borel-Rinkes I, Ledermann JA, et al. Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial. JNCI: Journal of the National Cancer Institute 2017;109. https://doi.org/10.1093/jnci/djx015.\u003c/li\u003e\n\u003cli\u003e Yamamoto T, Niibe Y, Aoki M, Shintani T, Yamada K, Kobayashi M, et al. Analyses of the local control of pulmonary Oligometastases after stereotactic body radiotherapy and the impact of local control on survival. BMC Cancer 2020;20:997. https://doi.org/10.1186/s12885-020-07514-9.\u003c/li\u003e\n\u003cli\u003e Chmura S, Winter KA, Robinson C, Pisansky TM, Borges V, Al-Hallaq H, et al. Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases. JAMA Oncol 2021;7:845. https://doi.org/10.1001/jamaoncol.2021.0687.\u003c/li\u003e\n\u003cli\u003e Palma DA, Olson R, Harrow S, Correa RJM, Schneiders F, Haasbeek CJA, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial. BMC Cancer 2019;19:816. https://doi.org/10.1186/s12885-019-5977-6.\u003c/li\u003e\n\u003cli\u003e Ashram S, Bahig H, Barry A, Blanchette D, Celinksi A, Chung P, et al. Planning Trade-offs for SABR in Patients With 4 to 10 Metastases: A Substudy of the SABR-COMET-10 Randomized Trial. International Journal of Radiation Oncology*Biology*Physics 2022;114:1011\u0026ndash;5. https://doi.org/10.1016/j.ijrobp.2022.05.035.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 Patients and disease characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eN. patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eN. oligometastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAge, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e67.8 (28.0 \u0026ndash; 87.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003eMale\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e80 (58.8)\u003c/p\u003e\n \u003cp\u003e56 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePerformance status\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e91 (66.9)\u003c/p\u003e\n \u003cp\u003e36 (26.5)\u003c/p\u003e\n \u003cp\u003e9 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePrimary tumor\u003c/p\u003e\n \u003cp\u003eColorectal\u003c/p\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003cp\u003eProstate\u003c/p\u003e\n \u003cp\u003eBreast\u003c/p\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e60 (44.1)\u003c/p\u003e\n \u003cp\u003e16 (11.8)\u003c/p\u003e\n \u003cp\u003e8 (5.9)\u003c/p\u003e\n \u003cp\u003e7 (5.1)\u003c/p\u003e\n \u003cp\u003e45 (33.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003cp\u003eNon-adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e110 (80.8)\u003c/p\u003e\n \u003cp\u003e26 (19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eDisease free interval, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e14.1 months (0 \u0026ndash; 222.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTiming of metastases\u003c/p\u003e\n \u003cp\u003eSynchronous\u003c/p\u003e\n \u003cp\u003eMetachronous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e39 (28.7)\u003c/p\u003e\n \u003cp\u003e97 (71.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eESTRO-EORTC classification\u003c/p\u003e\n \u003cp\u003e1 De novo sincrono\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 De novo metacrono oligorecurrence\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 De novo metacrono oligoprogression\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 Repeat oligorecurrence\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 Induced oligorecurrence\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 Induced oligopersistence\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 Induced oligoprogression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (4.4)\u003c/p\u003e\n \u003cp\u003e20 (14.7)\u003c/p\u003e\n \u003cp\u003e2 (1.5)\u003c/p\u003e\n \u003cp\u003e25 (18.4)\u003c/p\u003e\n \u003cp\u003e59 (43.4)\u003c/p\u003e\n \u003cp\u003e16 (11.8) \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (5.9) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePrevious local treatment\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e82 (60.3)\u003c/p\u003e\n \u003cp\u003e54 (39.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePrevious systemic therapy\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003e1 line\u003c/p\u003e\n \u003cp\u003e2 lines\u003c/p\u003e\n \u003cp\u003e3 or more lines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36 (26.5)\u003c/p\u003e\n \u003cp\u003e43 (31.6)\u003c/p\u003e\n \u003cp\u003e35 (25.7)\u003c/p\u003e\n \u003cp\u003e22 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTreated metastases\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e102 (75.0)\u003c/p\u003e\n \u003cp\u003e26 (19.1)\u003c/p\u003e\n \u003cp\u003e8 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTotal tumor volume in cc, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e19.1 (0.6 \u0026ndash; 245.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTreated site\u003c/p\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003cp\u003eLymph node\u003c/p\u003e\n \u003cp\u003eLung and lymph node\u003c/p\u003e\n \u003cp\u003eLung and liver\u003c/p\u003e\n \u003cp\u003eLiver and lymph node\u003c/p\u003e\n \u003cp\u003eOther (adrenal glands, pancreas, spine and non-spinal bone)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47 (34.6)\u003c/p\u003e\n \u003cp\u003e31 (22.8)\u003c/p\u003e\n \u003cp\u003e19 (14.0)\u003c/p\u003e\n \u003cp\u003e11 (8.1)\u003c/p\u003e\n \u003cp\u003e10 (7.3)\u003c/p\u003e\n \u003cp\u003e7 (5.1)\u003c/p\u003e\n \u003cp\u003e11 (8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTreated organs\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e97 (71.3)\u003c/p\u003e\n \u003cp\u003e36 (26.5)\u003c/p\u003e\n \u003cp\u003e3 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003ePresence of extra-target disease\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e119 (87.5)\u003c/p\u003e\n \u003cp\u003e17 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eConcomitant systemic therapy\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eAnti-EGFR\u003c/p\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003cp\u003eHormonal therapy / New generation hormonal therapy\u003c/p\u003e\n \u003cp\u003eTKI\u003c/p\u003e\n \u003cp\u003eImmunotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e102 (75.0)\u003c/p\u003e\n \u003cp\u003e34 (25.0)\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eDose in terms EQD2, median (range)\u003c/p\u003e\n \u003cp\u003e- EQD2 \u0026lt; 50 Gy\u003c/p\u003e\n \u003cp\u003e- EQD2 \u0026gt; 50 Gy to 70 Gy\u003c/p\u003e\n \u003cp\u003e- EQD2 \u0026gt; 70 Gy to 100 Gy\u003c/p\u003e\n \u003cp\u003e- EQD2 \u0026gt; 100 Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e83.3 (37.5 \u0026ndash; 218.7)\u003c/p\u003e\n \u003cp\u003e18 (13.2)\u003c/p\u003e\n \u003cp\u003e39 (28.7)\u003c/p\u003e\n \u003cp\u003e64 (47.1)\u003c/p\u003e\n \u003cp\u003e15 (11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Univariate and multivariable analysis for Overall survival and Progression free survival.\u0026nbsp;\u003c/strong\u003eValues in bold are statistically significant.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" valign=\"top\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eProgression free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.01 \u0026ndash; 1.05\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99 \u0026ndash; 1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.68 \u0026ndash; 1.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.709\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.69 \u0026ndash; 1.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.977\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePerfomance status, continuous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.87\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.33 \u0026ndash; 2.61\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99 \u0026ndash; 1.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePrimary tumor, colorectal vs other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.47 \u0026ndash; 1.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.206\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.54 \u0026ndash; 1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.167\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDisease free interval, months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99 \u0026ndash; 1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.868\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99 \u0026ndash; 1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.438\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSynchronous vs metachronous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.45 \u0026ndash; 1.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.55 \u0026ndash; 1.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.351\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePrevious LAT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.49 \u0026ndash; 1.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.349\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.85 \u0026ndash; 1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.271\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber treated mets:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003econtinuous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.72 \u0026ndash; 1.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.907\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.72 \u0026ndash; 1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.863\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 vs\u0026nbsp;\u0026ge;\u0026nbsp;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.57 \u0026ndash; 1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.925\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.66 \u0026ndash; 1.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.998\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;4 vs 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.39 \u0026ndash; 2.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.988\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.42 \u0026ndash; 1.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.686\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber treated organs, continuous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.62\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.08 \u0026ndash; 2.45\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.019\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.49\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.08 \u0026ndash; 2.06\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTreated site, Lung vs other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.65 \u0026ndash; 1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.860\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.79 \u0026ndash; 1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.461\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTreated site, liver vs other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.41 \u0026ndash; 1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.67\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.46 \u0026ndash; 0.97\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.036\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eExtratarget disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.36 \u0026ndash; 1.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.673\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.81 \u0026ndash; 2.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.235\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMinimum EQD2:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003econtinuous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.98\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.97 \u0026ndash; 0.99\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.024\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.99\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.98 \u0026ndash; 0.99\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.031\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;50 vs \u0026gt; 50 Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.46\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.24 \u0026ndash; 0.90\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.023\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.56\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.32 \u0026ndash; 0.97\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.040\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;70 vs \u0026gt; 70 Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.33 \u0026ndash; 0.85\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.65\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.45 \u0026ndash; 0.93\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.020\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;100 vs \u0026gt; 100 Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.54 \u0026ndash; 1.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.945\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.55 \u0026ndash; 1.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.822\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal tumor volume:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003econtinuous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.00\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.00 \u0026ndash; 1.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.00\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.00 \u0026ndash; 1.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;5 vs \u0026gt; 5\u0026nbsp;cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.00 \u0026ndash; 5.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.90 \u0026ndash; 2.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;10 vs \u0026gt; 10\u0026nbsp;cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.88\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.47 \u0026ndash; 5.63\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.95 \u0026ndash; 2.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026le;\u0026nbsp;50 vs \u0026gt; 50\u0026nbsp;cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.83\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.70 \u0026ndash; 4.69\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.93\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.26 \u0026ndash; 2.96\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" valign=\"top\"\u003e\n \u003cp\u003eMultivariable analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eProgression free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99 \u0026ndash; 1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePerformance status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.93 \u0026ndash; 2.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber treated organs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.86 \u0026ndash; 1.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.93 \u0026ndash; 1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTreated site, liver vs other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.48 \u0026ndash; 1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.107\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMinimum EQD2,\u0026nbsp;\u0026le;\u0026nbsp;50 vs \u0026gt; 50 Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.27 \u0026ndash; 1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.32 \u0026ndash; 1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal tumor volume,\u0026nbsp;\u0026le;\u0026nbsp;10 vs \u0026gt; 10 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.18 \u0026ndash; 4.78\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.014\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal tumor volume,\u0026nbsp;\u0026le;\u0026nbsp;50 vs \u0026gt; 50 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.63\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.05 \u0026ndash; 2.54\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.028\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"oligometastatic, SBRT, SABR, stereotactic radiotherapy, oligometastases, multiple, radiosurgery, stereotactic ablative radiotherapy ","lastPublishedDoi":"10.21203/rs.3.rs-2835255/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2835255/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Delivering stereotactic ablative radiotherapy (SABR) in patients with multiple oligometastases represents a challenge for clinical and technical reasons. We aimed to evaluate the outcome of patients affected by multiple oligometastases treated with SABR and the impact of tumor volume on survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and methods: \u003c/strong\u003eWe included all the patients treated with single course SABR for 3 to 5 extracranial oligometastases. All patients were treated with the volumetric modulated arc therapy (VMAT) technique with ablative intent. End-points of the analysis were overall survival (OS), progression free survival (PFS), local control (LC) and toxicity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e136 patients were treated from 2012 to 2020 on 451 oligometastases. Most common primary tumor was colorectal cancer (44.1%) followed by lung cancer (11.8%). A total of 3, 4 and 5 lesions were simultaneously treated in 102 (75.0%), 26 (19.1%), and 8 (5.9%) patients, respectively. Median total tumor volume (TTV) was 19.1 cc (range 0.6 - 245.1). With a median follow-up of 25.0 months, OS at 1 and 3 years was 88.4% and 50.2%, respectively. Increasing TTV was independent predictive factor of worse OS (HR 2.37, 95%CI 1.18 – 4.78, p=0.014) and PFS (HR 1.63, 95%CI 1.05 – 2.54; p=0.028). Median OS was 80.6 months if tumor volume was ≤ 10 cc (1 and 3 years OS rate 93.6% and 77.5%, respectively), and 31.1 months if TTV was higher than 10 cc (1 and 3 years OS rate 86.7% and 42.3%, respectively). Rates of LC at 1 and 3 years were 89.3% and 76.5%. In terms of toxicity, no grade 3 or higher toxicity was reported both in the acute and late settings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e We demonstrated the impact of tumor volume on survival and disease control of patients affected by multiple oligometastases treated with single course SABR.\u003c/p\u003e","manuscriptTitle":"Total tumor volume as a predictor of survival in patients with multiple oligometastases treated with stereotactic ablative radiotherapy (SABR)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-26 19:24:20","doi":"10.21203/rs.3.rs-2835255/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2023-06-02T08:03:10+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"403611b7-273b-4d45-b80e-13ab2bad3186","date":"2023-05-08T12:07:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"0a77c7fd-847d-4145-b78b-fd9d8b84ab48","date":"2023-04-27T17:13:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-04-21T16:10:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-04-21T16:04:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-04-21T02:46:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cancer Research and Clinical Oncology","date":"2023-04-19T07:21:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"cf552345-8eb9-4b51-8171-9bbb2170a365","owner":[],"postedDate":"April 26th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T22:04:49+00:00","versionOfRecord":{"articleIdentity":"rs-2835255","link":"https://doi.org/10.1007/s00432-023-04964-z","journal":{"identity":"journal-of-cancer-research-and-clinical-oncology","isVorOnly":false,"title":"Journal of Cancer Research and Clinical Oncology"},"publishedOn":"2023-06-06 21:07:02","publishedOnDateReadable":"June 6th, 2023"},"versionCreatedAt":"2023-04-26 19:24:20","video":"","vorDoi":"10.1007/s00432-023-04964-z","vorDoiUrl":"https://doi.org/10.1007/s00432-023-04964-z","workflowStages":[]},"version":"v1","identity":"rs-2835255","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2835255","identity":"rs-2835255","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}