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

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. 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. 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. We demonstrated the impact of tumor volume on survival and disease control of patients affected by multiple oligometastases treated with single course SABR.


Introduction
The oligometastatic state was first defined in 1995 as an intermediate state between localized and widespread diffuse disease (Hellman and Weichselbaum 1995). 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 . 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. 2016) 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 1 3 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. 2018) 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 (Decaestecker et al. 2014;Gomez et al. 2019;Ost et al. 2017;Phillips et al. 2020), 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 (Meyer et al. 2018;Franzese et al. 2018;Ouyang et al. 2019;Muldermans et al. 2016;Chalkidou et al. 2021). 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 ) 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 (Park et al. 2008): BED was calculated with a α/β of 10. The equivalent dose in 2 Gy 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%). Fiftyfour (39.7%) patients had previous local treatment before BED (Gy) =dose per fraction × number of fractions  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 Fig. 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.
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. 2013) 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. 2018) 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. 2022), 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 highdose radiotherapy. This concern is reflected by the majority of the studies published on the oligometastatic disease. Chalkidou et al. (2021) 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 (Palma et al. 2020) 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 (Lewis et al. 2017), 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. 2014) 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) (Ruers et al. 2017). In a large study published by (Yamamoto et al. 2020) 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 (Chmura et al. 2021). The on-going SABR-COMET-10 (Palma et al. 2019) 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 (Ashram et al. 2022).
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.
Funding No fundings were used for the present study.

Data availability
The data that support the findings of this study are available from the corresponding author, CF, upon reasonable request.